Clinical trial NCT03401190
Conditions: Acute Pancreatitis Systemic Inflammatory Response Syndrome
Sponsor: CalciMedica, Inc.
Start date: 2018-03-12; Completion date: 2019-04-30
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This open-label, dose-response study will evaluate the safety and efficacy of CM4620-IE in patients with acute pancreatitis and accompanying SIRS. The study will consist of two phases. The first phase will consist of 4 female and 4 male patients (cohorts 1 and 2, respectively), enrolled concurrently, randomized in a 3:1 ratio to receive CM4620-IE plus standard of care versus standard of care alone. Planned doses for first phase will be CM4620-IE 1.0 mg/kg on Day 1 and then 1.4 mg/kg on Days 2 - 4.

The second phase will consist of 8 female and 8 male patients (cohorts 3 and 4, respectively), enrolled concurrently, randomized in a 3:1 ratio to receive CM4620-IE plus standard of care versus standard of care alone. Planned doses for second phase will be CM4620-IE 2.08 mg/kg on Days 1 and 2 and then 1.6 mg/kg on Days 3 and 4. Dose escalation to second phase would only occur if needed for efficacy reasons and if no events suggesting a safety signal would occur with higher dosing.

The study is not powered for the analysis of study data with inferential statisitcs as the primary purpose of the study is to explore what endpoints would be most appropriate for future trials.

Detailed description:
After review of the efficacy, tolerability and safety data from cohorts 1 and 2 by the sponsor and the United States Food and Drug Administration, the decision was made to continue the low-dose regimen (CM4620-IE 1.0 mg/kg on Day 1 and then 1.4 mg/kg on Days 2 - 4) in cohort 3. Cohort 4 received the high-dose regimen (CM4620-IE 2.08 mg/kg on Days 1 and 2 and then 1.6 mg/kg on Days 3 and 4) as planned. Efficacy analysis were combined because no dose escalation occurred in cohort 3.

Patients were followed for 90 days after randomization.

Arms: arm 1: Phase 1: Cohorts 1 \& 2 will consist of 4 female and 4 male patients enrolled concurrently who will be randomized 3:1 to receive CM4620-IE plus standard of care versus standard of care alone. Planned doses for patients who are randomized to receive CM4620-IE are 1.0 mg/kg on Days 1 and 1.4 mg/kg on Days 2-4. arm 2: Phase 2: Cohorts 3 \& 4 will consist of 8 female and 8 male patients enrolled concurrently who will be randomized 3:1 to receive CM4620-IE plus standard of care versus standard of care alone. Planned doses for patients who are randomized to receive CM4620-IE are 2.08 mg/kg of CM4620-IE on Days 1 and 2, and 1.6 mg/kg on Days 3 and 4. arm 3: For all cohorts, patients will be randomized 3:1 to CM4620-IE plus standard of care versus standard of care alone.
Interventions: intervention 1: CM4620 Injectable Emulsion (Low Dose) intervention 2: CM4620 Injectable Emulsion (High Dose)
Intervention descriptions: intervention 1: CM4620-IE 1.0 mg/kg on Day 1 and then 1.4 mg/kg on Days 2-4, during the first phase of the study (Cohorts 1 and 2). All doses of CM4620-IE will be administered intravenously (IV) over 4 hours. intervention 2: CM4620-IE 2.08 mg/kg on Days 1 and 2 and then 1.6 mg/kg on Days 3 and 4, during the second phase of the study (Cohorts 3 and 4). All doses of CM4620-IE will be administered intravenously (IV) over 4 hours.

Protocol documents:
Prot_000.pdf: 
1 
 
CM4620-201 
An Open-Label, Dose-Response Study of 
CM4620 Injectable Emulsion in 
Patients with Acute Pancreatitis and Accompanying 
Systemic Inflammatory Response Syndrome (SIRS)  
Sponsor: 
CalciMedica, Inc. 
 
505 Coast Boulevard South, Suite 202 
 
La Jolla, CA 92037 
Sponsor Medical Contact: Sudarshan Hebbar, MD 
 
(816) 838-7105 – Mobile 
 
sudarshan@CalciMedica.com – Email 
FOR QUALIFIED INVESTIGATORS AND THEIR IRB ONLY 
Version: 4.0 
Issue Date: December 18, 2018 
Confidentiality Statement 
The information contained in this document is confidential and proprietary property 
of CalciMedica, Inc. Any distribution, copying, or disclosure is strictly prohibited unless 
federal regulations or state law requires such disclosure. Prior written authorization of 
CalciMedica, Inc. is required for any disclosure or use of the information contained herein. 
Persons to whom the information is disclosed must know that it is confidential and that it may 
not be further disclosed by them. 


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PRINCIPAL INVESTIGATOR STATEMENT OF AGREEMENT 
I, the undersigned Principal Investigator, have read and understood the foregoing protocol and its 
appendices. 
I have read, understood and signed the Statement of Investigator Form FDA-1572 that outlines my 
responsibilities as Principal Investigator. 
I have read and understood the provisions of Title 21 of the Code of Federal Regulations Part 312, 
Subpart D regarding responsibilities of Sponsors and Investigators; and Part 50 regarding 
protection of human patients and informed consent. 
I promise to abide by all applicable laws and regulations, and agree that, in all cases, the most 
restrictive regulation related to a given aspect of research involving protection of human patients 
will be followed. In the event I have a question regarding my obligations during the conduct of 
this protocol, I have ready access to these aforementioned regulations, as either my personal copy, 
or available on file from the Chairperson of the IRB or CalciMedica, and,  
I am authorized to enter into this commitment to conduct the study outlined in this protocol, and 
my signature below signifies that I agree to conduct the study as outlined herein. 
Printed Name of Principal Investigator 
Signature of Principal Investigator 
Date 


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SPONSOR APPROVAL AND SIGNATURE PAGE 
Sudarshan Hebbar M.D. 
Chief Medical Officer 
Date 
Kenneth A. Stauderman Ph.D. 
Chief Scientific Officer 
Date 
19-Dec-2018
19-Dec-2018


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SYNOPSIS 
Protocol 
Number: 
CM4620-201 
Protocol Title: 
An Open-Label, Dose-Response Study of CM4620 Injectable Emulsion 
(CM4620-IE) in Patients with Acute Pancreatitis and Accompanying 
Systemic Inflammatory Response Syndrome (SIRS) 
Sponsor: 
CalciMedica, Inc. 
505 Coast Blvd. South, Suite 202 
La Jolla, CA 92037 USA 
Study Phase: 
2 
Number of 
Patients and 
Sites: 
Approximately 24 patients with acute pancreatitis and accompanying SIRS 
or Hypoxemia will be randomized at approximately 10 sites. 
CM4620-IE Dose 
and Route of 
Administration: 
During the first phase of the study, the dose of CM4620-IE will be 1.0 
mg/kg on Day 1 and then 1.4 mg/kg on Days 2-4. During the second phase 
of the study, the dose of CM4620-IE is expected to be 2.08 mg/kg on Days 
1 and 2 and then 1.6 mg/kg on Days 3 and 4. All doses of CM4620-IE will 
be administered intravenously (IV) over 4 hours. 
Objectives: 
Primary: 
• To assess the safety and tolerability of CM4620-IE in patients with 
acute pancreatitis and accompanying SIRS or Hypoxemia. 
Secondary: 
• To assess the efficacy of CM4620-IE in patients with acute pancreatitis 
and accompanying SIRS or Hypoxemia. 
• To determine the pharmacokinetic profile of CM4620-IE in patients 
with acute pancreatitis and accompanying SIRS or Hypoxemia. 
Inclusion 
Criteria: 
Patients must meet all of the following criteria to be randomized in a 
cohort: 
1. Diagnosis of acute pancreatitis established by the presence of 
abdominal pain consistent with acute pancreatitis and 1 of the 
following 2 criteria:  
a. Serum lipase or serum amylase > 3 times the upper limit of normal 
(ULN); 
b. Characteristic findings of acute pancreatitis on abdominal imaging; 


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2. One of the following 2 criteria, either: 
a. ASpO2 <96% with a FiO2 of 21% (room air) to 27% or a SpO2 
<97% with a FiO2 ≥28%; Or 
b. Diagnosis of SIRS, defined by the presence of at least 2 of the 
following 4 criteria: 
i. 
Temperature < 36°C or > 38°C; 
ii. 
Heart rate > 90 beats/minute; 
iii. 
Respiratory rate >20 breaths/minute or arterial carbon 
dioxide tension (PaCO2) <32 mmHg; 
iv. 
White blood cell count (WBC) >12,000 mm3, or <4,000 
mm3, or > 10% immature (band) forms; 
3. No evidence of pancreatic necrosis on contrast-enhanced computed 
tomography (CECT) performed in the 18 hours prior to consent or 
after consent and before Day 1; 
4. Adults ≥ 18 years of age; 
5. A female patient of child bearing potential who is sexually active with 
a male partner must be willing to practice acceptable methods of birth 
control for 365 days after the last dose of CM4620-IE; 
6. A male patient who is sexually active with a female partner of 
childbearing potential must be willing to practice acceptable methods 
of birth control for 365 days after the last dose of CM4620-IE and 
must not donate sperm for 365 days; 
7. Willing and able to, or have a legal authorized representative (LAR) 
that is willing and able to, provide informed consent to participate, and 
to cooperate with all aspects of the protocol. 
Exclusion 
Criteria: 
Patients with any of the following conditions or characteristics must be 
excluded from enrolling in a cohort: 
1. Any concurrent clinical condition that a study physician believes could 
potentially pose an unacceptable health risk to the patient while 
involved in the study, including a CV SOFA score of 4 at the time of 
screening, or may limit expected survival to <6 months: 
2. Suspected presence of cholangitis in the judgment of the treating 
investigator; 
3. ERCP performed in the previous 7 days; 
4. Any malignancy being treated with chemotherapy or immunotherapy; 


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5. Any autoimmune disease being treated with immunosuppressive 
medication or immunotherapy (Section 5.3 for list of prohibited 
medications); 
6. History of: 
a. Chronic pancreatitis, pancreatic necrosis or necrosectomy, or 
pancreatic enzyme replacement therapy; 
b. Biopsy proven cirrhosis, portal hypertension, hepatic 
failure/hepatic encephalopathy; 
c. Known hepatitis B or C, or HIV; 
d. History of organ or hematologic transplant; 
e. Resuscitated cardiac arrest, myocardial infarction, 
revascularization, cardiovascular accident (CVA) in the 30 days 
prior to Day 1; 
7. Current renal replacement therapy; 
8. Current known abuse of cocaine or methamphetamine; 
9. Known to be pregnant or are nursing; 
10. Participated in another study of an investigational drug or therapeutic 
medical device in the 30 days prior to Day 1; 
11. History of allergy to eggs or known hypersensitivity to any 
components of CM4620-IE. 
Study Design: 
This open-label, dose-response study will evaluate the safety and efficacy 
of CM4620-IE in patients with acute pancreatitis and accompanying SIRS 
or hypoxemia. The study will consist of two phases. The first phase will 
consist of 2 cohorts that will be enrolled concurrently. Cohort 1 will 
consist of 4 female patients who will be randomized 3:1 to receive 
CM4620-IE plus supportive care versus supportive care alone. Cohort 2 
will consist of 4 male patients who will be randomized 3:1 to receive 
CM4620-IE plus supportive care versus supportive care alone. Planned 
doses for patients in both cohorts who are randomized to receive CM4620-
IE are 1.0 mg/kg on Days 1 and 1.4 mg/kg on Days 2-4. The first infusion 
of CM4620-IE must be started preferably within 6 (up to 8) hours of the 
patient or LAR providing informed consent and should be administered IV 
over 4 hours. Subsequent infusions will be started every 24 hours (± 1 
hour) from the start of the first infusion. 
 
The second phase will consist of 2 cohorts. Cohort 3 will consist of 
8 female patients who will be randomized 3:1 to receive CM4620-IE plus 
supportive care versus supportive care alone. Cohort 4 will consist of 
8 male patients who will be randomized 3:1 to receive CM4620-IE plus 


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supportive care versus supportive care alone. Planned doses for patients in 
both cohorts who are randomized to receive CM4620-IE are 2.08 mg/kg of 
CM4620-IE on Days 1 and 2, and 1.6 mg/kg on Days 3 and 4. The first 
infusion of CM4620-IE must be started within 6 (up to 8) hours of the 
patient or LAR providing informed consent and will be administered 
intravenously IV over 4 hours. Subsequent infusions will be started every 
24 hours (± 1 hour) from the start of the first infusion. 
 
The decision to start Cohort 3 will be made after CalciMedica reviews the 
available efficacy, safety and tolerability data from Cohort 1 and discusses 
with the Principal Investigators. The decision to start Cohort 4 in the 
second phase of the study will be made after CalciMedica reviews the 
available efficacy, safety and tolerability data from Cohort 2 and discusses 
with the Principal Investigators. 
 
For all 4 cohorts, a study physician or appropriately trained delegate will 
perform all assessments daily through Day 10, or until discharge 
if occurring earlier. After Day 10, and starting on Day 12, serious adverse 
events (SAEs) will be captured every 48 hours until Day 30 (± 2 days), or 
until discharge if occurring earlier. Patients discharged prior to Day 30 will 
be contacted on Day 30 (± 2 days) to capture SAEs and any re-admissions 
to the hospital. Patients will also be contacted on Day 90 (± 7 days) to 
assess mortality. 
 
It is recommended that all patients in the study should receive supportive 
care consistent with the 2013 International Association of Pancreatology 
(IAP)/American Pancreatic Association (APA) evidence-based guidelines 
for the management of acute pancreatitis, and local standard of care (SOC) 
for the management of other medical conditions. Fluid resuscitation should 
be provided to all patients as recommended in the guidelines; lactated 
Ringer’s solution may be the preferred replacement fluid for patients with 
acute pancreatitis. Other than at Screening, and all venous and arterial 
blood gas testing, the blood samples for laboratories collected as part of 
the protocol, will be tested at a central lab, and will not be available to 
assist the PI or treating physician in managing the patient. The PI or 
treating physician will order all laboratory testing necessary for the 
management of the patient and analysis of these samples will be performed 
at the local laboratory. 
 
All patients randomized in the study will undergo a CECT of the pancreas 
at Screening and on Day 5. The Day 5 CECT will be performed on Days 6 
or 7 if unable to be performed on Day 5. The Screening CECT may have 
been performed more than 18 hours prior to consent and not repeated after 
consent for patient-specific safety considerations. The PI or treating 
physician may elect to change the timing of the CECT to later than Day 7 


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due to patient-specific safety considerations, but must inform the Medical 
Monitor of the decision to do so. The PI or treating physician may 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. 
Safety 
Assessments: 
Safety assessments will include the following: 
• Physical examinations 
• Vital signs measurements 
• Clinical laboratory measurements 
• Concomitant medications 
• Incidence, intensity and relationship of treatment-emergent adverse 
events (TEAEs) and SAEs. 
Efficacy 
Assessments: 
Efficacy assessments will include the following: 
• SIRS score 
• APACHE II score 
• CECT of the pancreas 
• Organ Failure score 
• Sequential Organ Failure Assessment (SOFA) score 
• Biomarker measurements including, but not limited to, C-Reactive 
Protein (CRP), D-Dimer, Procalcitonin, urine NGAL, Il-6, and Il-8 
• Pain Numeric Rating Scale (PNRS) score 
• Critical-Care Pain Observation Tool (CPOT) score 
Pharmacokinetic 
Assessments: 
Samples for pharmacokinetic assessment will be obtained prior to infusion 
of CM4620-IE and after completion of CM4620-IE administration on 
selected days. 
Statistical 
Considerations 
A full Statistical Analysis Plan (SAP) detailing the primary and secondary 
efficacy analyses and the safety analyses, will be developed. This study is 
not powered for analysis of study data with inferential statistics. All data 
will be summarized using descriptive statistics only. Continuous data will 
be summarized with number of patients (n), mean, median, minimum, 
maximum, standard of deviation, coefficient of variation and or geometric 
mean. Categorical data will be summarized with number and proportion of 
patients. 
 
 


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Table of Contents 
Principal Investigator Statement of Agreement .............................................................................. 2 
Sponsor Approval and Signature Page ........................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
List of Tables ................................................................................................................................ 12 
List of Figures ............................................................................................................................... 12 
List of Terms and Abbreviations .................................................................................................. 13 
1 
INTRODUCTION ................................................................................................................. 15 
1.1 
Acute Pancreatitis ....................................................................................................... 15 
1.2 
Pathophysiology of Acute Pancreatitis ....................................................................... 16 
1.3 
Overview of CM4620 ................................................................................................. 18 
1.4 
Pre-Clinical Development of CM4620 ....................................................................... 18 
1.4.1 
Pre-Clinical Safety and Toxicology Studies .................................................. 18 
1.4.2 
Preclinical Efficacy Studies ........................................................................... 19 
1.5 
Clinical Development of CM4620-IE ......................................................................... 20 
1.6 
Rationale for the Study and Selected Doses ............................................................... 23 
2 
OBJECTIVES ........................................................................................................................ 24 
2.1 
Primary Objective ....................................................................................................... 24 
2.2 
Secondary Objectives .................................................................................................. 24 
3 
INVESTIGATIONAL PLAN ............................................................................................... 25 
3.1 
Study Design ............................................................................................................... 25 
3.2 
End of Study ............................................................................................................... 26 
3.3 
Sponsor or Regulatory Agency Termination of the Study .......................................... 26 
4 
SELECTION OF PATIENTS ............................................................................................... 27 
4.1 
Inclusion Criteria ........................................................................................................ 27 
4.2 
Exclusion Criteria ....................................................................................................... 28 
4.3 
Re-Screening ............................................................................................................... 28 
5 
TREATMENT OF PATIENTS ............................................................................................. 29 
5.1 
Overview ..................................................................................................................... 29 
5.2 
Discharge Criteria ....................................................................................................... 29 
5.3 
Prohibited Medications ............................................................................................... 30 


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5.4 
Compliance ................................................................................................................. 30 
6 
PROCEDURES ..................................................................................................................... 31 
6.1 
Randomization Procedures ......................................................................................... 31 
6.2 
Discontinuation and Withdrawal ................................................................................ 31 
7 
CM4620-IE MATERIALS AND MANAGEMENT ............................................................ 32 
7.1 
CM4620-IE Product Description ................................................................................ 32 
7.2 
CM4620-IE Storage .................................................................................................... 32 
7.3 
CM4620-IE Preparation .............................................................................................. 32 
7.4 
CM4620-IE Administration ........................................................................................ 33 
7.5 
Packaging and Labeling .............................................................................................. 33 
7.6 
Accountability, Handling and Disposal ...................................................................... 33 
8 
VISITS AND ASSESSMENTS ............................................................................................ 34 
8.1 
Screening..................................................................................................................... 34 
8.2 
Day 1 (0 hour to < 24 hours) ....................................................................................... 34 
8.3 
Day 2 (24 hours to <48 hours) .................................................................................... 35 
8.4 
Day 3 (48 hours to < 72 hours) ................................................................................... 36 
8.5 
Day 4 (72 hours < 96 hours) ....................................................................................... 37 
8.6 
Day 5 (96 hours to < 120 hours) ................................................................................. 37 
8.7 
Days 6 – 9 ................................................................................................................... 38 
8.8 
Day 10 ......................................................................................................................... 39 
8.9 
Days 12 – 30 ............................................................................................................... 39 
8.10 Day 90 ......................................................................................................................... 40 
8.11 Study Assessments ...................................................................................................... 40 
8.11.1 Medical History ............................................................................................. 40 
8.11.2 Concomitant Medications .............................................................................. 40 
8.11.3 Physical Examination .................................................................................... 40 
8.11.4 Glasgow Coma Scale Score ........................................................................... 40 
8.11.5 Vital Signs ..................................................................................................... 41 
8.11.6 Arterial Blood Gas ......................................................................................... 42 
8.11.7 Pulse Oximetry .............................................................................................. 42 
8.11.8 Pregnancy Testing ......................................................................................... 42 
8.11.9 Laboratory Analyses ...................................................................................... 43 


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8.11.10 PK analysis .................................................................................................... 43 
8.11.11 Biomarker Analysis ....................................................................................... 43 
8.11.12 Numeric Pain Rating Scale (PNRS) .............................................................. 43 
8.11.13 Critical-Care Pain Observation Tool ............................................................. 44 
8.11.14 Contrast-Enhanced Computed Tomography (CECT) of the Pancreas .......... 44 
8.11.15 Systemic Inflammatory Response Syndrome (SIRS) .................................... 45 
9 
ADVERSE EVENTS ............................................................................................................ 46 
9.1 
Definition of Adverse Event ....................................................................................... 46 
9.2 
Definition of Serious Adverse Event .......................................................................... 46 
9.3 
Eliciting Adverse Event Information .......................................................................... 47 
9.4 
Recording Adverse Events .......................................................................................... 47 
9.5 
Assessment of Relationship to CM4620-IE ................................................................ 48 
9.6 
Assessment of Severity ............................................................................................... 48 
9.7 
Reporting of Serious Adverse Events ......................................................................... 49 
9.8 
Suspected Pregnancy in a Woman of Childbearing Potential .................................... 50 
10 STATISTICAL ANALYSIS ................................................................................................. 51 
10.1 Sample Size ................................................................................................................. 51 
10.2 Study Assessments ...................................................................................................... 51 
10.3 Analysis Sets ............................................................................................................... 51 
10.4 Statistical Analyses Plan ............................................................................................. 52 
11 ADMINISTRATIVE CONSIDERATIONS ......................................................................... 53 
11.1 Electronic Case Report Forms .................................................................................... 53 
11.2 Monitoring of the Study .............................................................................................. 53 
11.3 Inspection of Records ................................................................................................. 53 
11.4 Study Record Retention .............................................................................................. 53 
11.5 Study Conduct: Good Clinical Practice and Declaration of Helsinki ......................... 53 
11.6 Responsibilities of the Investigator and the IRB/EC/REB ......................................... 54 
11.7 Confidentiality ............................................................................................................ 54 
11.8 Modification of the Protocol ....................................................................................... 54 
11.9 Informed Consent........................................................................................................ 55 
11.10 Protocol Violations and Deviations ............................................................................ 55 
11.11 Financial Disclosure .................................................................................................... 56 


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11.12 Sponsor Obligations .................................................................................................... 56 
11.13 Investigator Documentation ........................................................................................ 56 
11.14 Clinical Study Insurance ............................................................................................. 57 
11.15 Use of Information ...................................................................................................... 57 
11.16 Publications ................................................................................................................. 57 
12 REFERENCES ...................................................................................................................... 58 
Appendix 1 
Definition of Organ Failure .................................................................................. 60 
Appendix 2 
Sequential Organ Failure Assessment (SOFA) ..................................................... 61 
Appendix 3 
CTSI Score ............................................................................................................ 62 
Appendix 4 
Modified CTSI Score ............................................................................................ 63 
Appendix 5 
Revised Atlanta Classification of Acute Pancreatitis ........................................... 64 
Appendix 6 
Determinant Based Classification of Acute Pancreatitis Severity (DBCAPS) ..... 65 
Appendix 7 
IAP/APA Summary of Recommendations ........................................................... 66 
Appendix 8 
Pain Numeric Rating Scale (PNRS) ..................................................................... 71 
Appendix 9 
The Critical-Care Pain Observation Tool (CPOT) ............................................... 72 
Appendix 10 APACHE II Score ................................................................................................. 73 
Appendix 11 Schedule of Events ................................................................................................ 74 
 
List of Tables 
Table 1 
SAD (CM4620-101) ................................................................................................... 21 
Table 2 
MAD (CM4620-102) .................................................................................................. 22 
Table 3 
CM4620-IE Product Information ................................................................................ 32 
Table 4 
Glasgow Coma Scale Score ........................................................................................ 41 
Table 5 
Conversion of O2 Flow to FiO2 ................................................................................. 42 
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. ................. 17 
Figure 2. Sites of action of CM4620 in treating acute pancreatitis ............................................ 20 


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LIST OF TERMS AND ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine transaminase 
AP 
Acute Pancreatitis 
APACHE II 
Acute Physiology and Chronic Health Evaluation II 
AST 
Aspartate transaminase 
ATP 
Adenosine triphosphate 
BUN 
Blood urea nitrogen 
CCK 
Cholecystokinin 
CECT 
Contrast Enhanced Computed Tomography 
CGMO 
Current Good Manufacturing Practice 
CPOT 
Critical Care Pain Observation Tool 
CRF 
Case report form 
CRAC 
Calcium release-activated calcium 
CTSI 
Computed Tomography Severity Index 
CV 
Cardiovascular 
ECG 
Electrocardiogram 
EDTA 
Edetate disodium salt dehydrate 
ER 
Endoplasmic reticulum 
ERCP 
Endoscopic retrograde cholangiopancreatography 
FiO2 
Fraction of inspired oxygen 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyltransferase 
GFR 
Glomerular filtration rate 
HED 
Human equivalent dose 
Hr(s) 
Hour(s) 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
Kg 
Kilogram 
L 
Liter 
LAR 
Legal authorized representative 
MAD 
Multiple ascending dose 


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Abbreviation 
Definition 
MPO 
Myeloperoxidase 
NOAEL 
No observable adverse effect level 
PNRS 
Pain numeric rating scale 
PEEP 
Positive end-expiratory pressure 
PK 
Pharmacokinetic 
PP 
Per protocol 
QTcF 
QT corrected for HR using Fridericia's method 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SaO2 
Arterial blood oxygen saturation measured directly 
SAP 
Statistical analysis plan 
SIRS 
Systemic inflammatory response syndrome 
SOC 
Standard of care 
SOCE 
Store-operated calcium entry 
SOFA 
Sequential organ failure assessment 
SOP 
Standard operating procedures 
SpO2 
Oxyhemoglobin percent saturation measured by pulse oximetry 
VTBI 
Volume to be infused 
WBC 
White blood cell 
μg 
microgram 
 
 


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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 potentially systemic, inflammation, and the latter by a 
compensatory immunosuppressive 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 acute pancreatitis, moderately 
severe AP, and severe acute pancreatitis (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 ≥ 48 hours. Local complications include 
peripancreatic fluid 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 ‘determinant-based classification of severity’, has been proposed as an 
alternative to the Atlanta 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 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, and rarely of the 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 by up to 100-fold (Petersen 2006). 
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 
factors and drugs. A small residual group has no obvious cause and is labelled ‘‘idiopathic.’’ 
However, many of these may be due to unidentified microlithiasis (cholesterol crystals, biliary 


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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 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 Ca2+ in pancreatic 
acinar cells, provided by Ca2+ release from internal stores such as the endoplasmic reticulum 
(ER) (Petersen 2011). 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 
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). 


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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, which limits the cell’s ability to handle stress and further promotes 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. 
 
 
 
Ca2+
Orai1
IP3R
Ca2+
ER Ca2+ stores
STIM1
STIM1
EF hand
Ca2+
Endoplasmic
Reticulum
Bile acids; Alcohol metabolites 
Mitochondria
Zymogen
granules
Response
Activation of digestive enzymes
Mitochondrial function, ATP levels
Cytokine production
Cell injury and necrosis
CRAC Channel Inhibitors
PANCREATIC ACINAR CELLS
Gallstones
Alcohol


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1.3 
Overview of CM4620 
CM4620 is a potent and selective inhibitor of CRAC channels. CRAC channels are composed of 
the pore-forming plasma membrane protein Orai1 and the calcium-sensing ER gating-protein 
STIM1. Low levels of calcium within the ER cause the STIM1 protein to oligomerize and move 
to locations closely apposed to Orai1. When STIM1 binds to Orai1, the Orai1 Ca2+ pore opens, 
permitting entry of extracellular calcium into the cell through the CRAC channel. This process is 
referred to as SOCE and evidence suggests that SOCE through CRAC channels plays a critical 
role in the degradation and necrosis of pancreatic acinar cells in patients with AP. 
The potential for CM4620 to inhibit CRAC channels was investigated by measuring the 
electrophysiological current (ICRAC) associated with calcium entry through CRAC channels in 
HEK293 cells stably expressing recombinant human Orai1/STIM1. Cellular recordings were 
performed using the whole-cell patch clamp method. Measurements of ICRAC were made after the 
addition of extracellular 10 mM calcium chloride and subsequent administration of CM4620 at 
concentrations of 0.001, 0.01, 0.1, and 1 µM. CM4620 was able to inhibit ICRAC in a 
concentration-dependent manner, producing a mean 50% inhibition (IC50) value of 119 nM. 
Rapid and complete inhibition was achieved at 1 µM of CM4620. Evaluations were performed to 
further elucidate the site of action of CM4620. A mutation in Orai1 (Orai1-V102C) is known to 
produce constitutively active CRAC channels without the need for STIM1. In this evaluation, 
successive concentrations of CM4620 produced nearly complete inhibition of the STIM1-
independent ICRAC, indicating that Orai1 is a major site of action of the compound. 
1.4 
Pre-Clinical Development of CM4620 
1.4.1 
Pre-Clinical Safety and Toxicology Studies 
Safety pharmacology studies conducted in rats indicated no CM4620-induced adverse effects on 
central nervous or respiratory systems. Dose-limiting adverse clinical and cardiovascular effects 
were noted in a single telemetered cynomolgus monkey dosed at 25 mg/kg IV with CM4620-IE. 
Cardiovascular data at lower doses (1, 3 and 10 mg/kg) showed transient, non-dose-related, 
slight-to-moderate increases in systolic/diastolic arterial blood pressures and negative 
chronotropic effects (mild and non-adverse) at all doses and in placebo treated animals.  
Repeat-dose toxicity studies conducted in both rats and monkeys showed no observable adverse 
effect levels (NOAELs) of 25 mg/kg/day and 3 mg/kg/day, respectively. In vitro genetic toxicity 
studies were negative in the Ames bacterial reverse mutation assay and weakly positive/equivocal 
in a micronucleus assay conducted in human peripheral blood lymphocytes. A subsequent in 
vivo micronucleus study conducted in rats involving two different endpoints (bone marrow 
micronucleus and liver Comet assays) showed no evidence of DNA reactivity. Based on the 
results of the complete battery of genotoxicity testing, the weight of evidence indicates that 
CM4620 is neither mutagenic nor clastogenic. Hemolysis testing concluded that CM4620 
placebo was compatible with human plasma and non-hemolytic in human blood. Specific local 
tolerance studies to examine irritation/inflammation at the injection site were not performed, but 
no evidence of compound-related or vehicle-related local irritation was observed in the repeat-


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dose toxicity studies in rat and monkey. Finally, in vitro 3T3 results indicated that CM4620 is 
potentially phototoxic, so appropriate precautions are being taken in clinical trials. 
1.4.2 
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, CM4620 can protect 
these cells from pancreatitis-induced cell death and can reduce biochemical, immunological and 
histopathologic consequences when administered early in the course of the disease. CM4620 
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 CM4620 has the potential to be effective in the treatment of AP 
regardless of the cause and support the administration of CM4620 as an IV infusion to humans. 
Additional non-clinical evidence supports the position that the effects of CM4620 on the 
pancreas are complimented by its ability to reduce inflammatory responses that can manifest 
clinically as SIRS.  
The protection offered by CM4620 in vitro has been confirmed in three diverse in vivo models 
representative of gallstone-, alcohol-, or hyper-stimulation–induced acute pancreatitis (TLCS-
induced, fatty acid ethyl ester [FAEE]-induced and caerulein-induced pancreatitis models, 
respectively). Trypsin activity within pancreatic tissue, myeloperoxidase 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 (caerulein-induced acute 
pancreatitis), two 5 or 20 mg/kg IP doses of CM4620 in the mouse (TLCS-induced and FAEE-
induced pancreatitis 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 (caerulein-induced pancreatitis model). The timing of CM4620 administration relative to 
induction of pancreatitis was investigated in the TLCS-induced and FAEE-induced pancreatitis 
models and the results suggest that CM4620 may be more effective in minimizing pancreatic 
injury and subsequent downstream events if it is administered early in the course of disease, 
although later administration retains effectiveness in halting disease progression (Wen 2015). 
The potential for CM4620 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, CM4620 
inhibited human neutrophil function and inhibited release of key inflammatory cytokines (IL-2, 
IFNγ and IL-17) in human lymphocytes (IC50 4-138 nM). Results from ex vivo pharmacodynamic 
analyses in blood demonstrated that CM4620 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 CM4620 on myeloperoxidase activity in the lung of mice in TLCS-induced and FAEE-
induced pancreatitis models and rats in the caerulein-induced pancreatitis model were assessed. 
Myeloperoxidase 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. 


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Two IP doses of CM4620 at 20 mg/kg in mice or one 4-hour infusion of CM4620 Nano-emulsion 
at 5 mg/kg in rats were able to substantially reduce lung myeloperoxidase activity (80% reduction 
in the mouse TLCS model, 73% reduction in the rat caerulein model). Lastly, in the IV infusion 
study in rats, CM4620 significantly reduced IL-6 and TNFα mRNA levels in both pancreas and 
lung, as well as that of myeloperoxidase. 
Figure 2 highlights the potential role of CM4620 in treating acute pancreatitis through its effects 
on both the acinar cell and the immune system: 
Figure 2. Sites of action of CM4620 in treating acute pancreatitis 
 
1.5 
Clinical Development of CM4620-IE 
CalciMedica has conducted two Phase 1 studies of CM4620-IE 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 CM4620-IE or placebo was administered via a 4-hour IV 
infusion. 


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Table 1 
SAD (CM4620-101) 
Group 
Active Treatment 
Number of Active 
Treatment Subjects 
Number of Placebo 
Treatment Subjects 
IV Dose Volume 
(mL/kg) 
1 
0.1 mg/kg 
6 
2 
1.3 
2 
0.24 mg/kg 
3 
1 
1.3 
3 
0.48 mg/kg 
3 
1 
1.3 
4 
1.0 mg/kg 
6 
2 
1.3 
5 
2.1 mg/kg 
6 
2 
1.3 
 
Of the 32 enrolled subjects, there were no serious adverse events (SAE) or adverse events (AE) 
classified as moderate or severe in intensity. There were three clinical AEs that were all 
classified as mild in intensity. Two of the AEs were considered possibly related and one was 
considered unlikely or unrelated to study treatment. In each case, no action was taken with 
respect to study treatment because of the AEs. No laboratory abnormalities were observed that 
were considered clinically significant. There were vehicle-related increases in serum triglyceride 
and cholesterol levels noted in some subjects that returned to baseline within 24 hours. There 
was no evidence of any sustained treatment related increase in systolic or diastolic blood 
pressure. In addition, cardiac function, monitored by continuous electrocardiographic recording 
and serial biomarker testing, showed no evidence of any treatment related effect on heart rate, 
QTcF, cardiac troponin-T or B-type natriuretic peptide levels.  
In the SAD study (CM4620-101), interim non-compartmental pharmacokinetic (PK) analysis 
indicates that CM4620 likely distributes to three compartments. Plasma concentrations of 
compound rise steadily during the 4-hour infusion, with Tmax achieved at the end of infusion 
(4 hours). After the end of infusion, there is a rapid and prominent distribution phase followed by 
a prolonged period of residual drug levels. The terminal elimination phase has not yet been fully 
characterized as it appears to be much longer than was anticipated based on pre-clinical PK data 
in mouse, rat, dog and monkey. Plasma concentrations during the terminal phase are 
approximately 5% of Cmax values and, as indicated above, to date there have been no clinically 
significant AEs reported during this phase. Plasma exposures, defined by AUC0-24h, appear to be 
dose-proportional and reached a maximum of 6710 ng*h/mL in Group 5, which is 4.3-fold below 
the mean AUC24h in monkey at the NOAEL (29,000 ng*hr/mL). 
In the MAD study (Table 2) of CM4620-IE (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. 


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Table 2 
MAD (CM4620-102) 
Group 
Active Treatment 
Daily for 7 days 
Number of Active 
Treatment Subjects 
Number of Placebo 
Treatment Subjects 
IV Dose Volume 
(mL/kg) 
1 
0.5 mg/kg 
5 
3 
0.3125a 
2 
1.0 mg/kg 
6 
2 
0.625 
a one placebo patient received maximum dose volume of 1.3 mL/kg 
 
Subjects in the second group of CM4620-102 were randomized to receive a single dose of active 
treatment, 1.0 mg/kg, versus placebo for seven consecutive days. Eight healthy subjects were 
enrolled in the second group, with six receiving active treatment and two receiving placebo for 
seven consecutive days. There were no SAEs and no AEs classified as moderate or severe in 
intensity. There were three AEs that were all classified as mild in intensity. In each case, no 
action was taken with respect to study treatment because of the AEs. No laboratory abnormalities 
were observed that were considered clinically significant. 
There were vehicle-related increases in serum triglyceride noted in some subjects in both groups 
with levels returning to baseline within 24 hours. Cholesterol levels accumulated in some 
subjects in both groups with daily dosing but the increases were not considered clinically 
significant and were related to the vehicle. Thus, the largest rise in cholesterol levels was in 
the subject who received placebo at the maximum dose volume of emulsion. The rise in 
cholesterol is believed to be due to the release of tissue cholesterol induced by the lecithin in 
the emulsion (Byers 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 CM4620 
accumulated in plasma, with a 2.6-fold increase in systemic exposure (AUC24h) on Day 7 
compared to Day 1 of dosing, consistent with modeling simulations. Cmax accumulated 1.6-fold 
(geometric mean of 363 ng/mL on Day 7). The geometric mean of the AUC24h on Day 7 was 
3190 ng*hr/mL, which is 9.1-fold below the NOAEL AUC24h in monkey (29,000 ng*hr/mL). PK 
analysis of Group 2 in CM4620-102 (1.0 mg/kg) indicates that CM4620 accumulated in plasma, 
with a 2.6-fold increase in AUC24h on Day 7 compared to Day 1 of dosing, consistent with 
modeling simulations. Cmax accumulated 1.4-fold (geometric mean 637 ng/mL on Day 7). The 
geometric mean of the AUC24h on Day 7 was 6830 ng*hr/mL, which is 4.2-fold below the 
NOAEL AUC24h in monkey (29,000 ng*hr/mL). After the end of 7 days of infusion, there 
remained a prolonged period of residual drug levels in both MAD groups that remained 
significantly lower than the Cmax on Day 7. 
Subjects in Groups 4 and 5 of the SAD study and Groups 1 and 2 of the MAD study who received 
CM4620 were followed for 1 year in a long-term extension study to assess for adverse events 
and serious adverse events. In addition, PK levels were drawn in all 4 groups on Day 270 to 
further characterize the terminal phase and the prolonged period of residual drug level. There 


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were no serious adverse events and no adverse events rated moderate or severe in intensity in 
subjects followed for 365 days. 
A population PK model was built using the data from the SAD and MAD studies. The model 
suggested three compartments for distribution as well as gender and body weight-dependent 
differences in exposures. The model showed that females have a higher volume of distribution 
compared to males, 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 identity the dosing 
regimens for the first and second phases of the study. 
1.6 
Rationale for the Study and Selected Doses 
An open-label study in patients with acute pancreatitis will be performed to further characterize 
the safety and pharmacokinetic profile of a higher exposure of CM4620-IE than obtained on 
Day 7 in the 5th group of the SAD and the 2nd group of the MAD. A 3rd group of healthy subjects 
in the MAD was not dosed, despite a benign safety profile, because of the prolonged period of 
residual drug levels noted in the previous groups of healthy subjects. CalciMedica believes, 
however, that a risk benefit analysis would support continued escalation of dosing in patients 
with acute pancreatitis given the potential for CM4620 to be efficacious in treating acute 
pancreatitis, especially with increasing exposures. The study will be open-label to provide 
investigators and CalciMedica the ability to immediately assess any AEs or SAEs and their 
relationship to CM4620-IE. There will be three dose groups in the open-label study: patients who 
receive no drug, patients who receive dosing of drug that would result in a mean plasma AUC24h 
after dosing on Day 4 similar to the mean AUC24h on Day 7 in the 5th group of the SAD study 
and the 2nd group of the MAD study, and patients who receive dosing of drug that would result in 
a mean plasma AUC24h on Day 4 that is 30% higher than that in Phase 1 of the open-label study. 
This design will allow a dose-response analysis of both safety and efficacy assessments. An 
equal number of females and males will be enrolled in all three dose groups to allow further 
characterization of the gender differences in drug exposure as well as safety and efficacy. 


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2 
OBJECTIVES 
2.1 
Primary Objective 
• To assess the safety and tolerability of CM4620-IE in patients with acute pancreatitis 
and accompanying SIRS or Hypoxemia 
2.2 
Secondary Objectives 
• To assess the efficacy of CM4620-IE in patients with acute pancreatitis and 
accompanying SIRS or Hypoxemia 
• To determine the pharmacokinetic profile of CM4620-IE in patients with acute 
pancreatitis and accompanying SIRS or Hypoxemia 


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3 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
This open-label, dose-response study will evaluate the safety and efficacy of CM4620-IE in 
patients with acute pancreatitis and accompanying SIRS or Hypoxemia. The study will consist of 
two phases. The first phase will consist of 2 cohorts that will be enrolled concurrently. Cohort 1 
will consist of 4 female patients who will be randomized 3:1 to receive CM4620-IE plus 
supportive care versus supportive care alone. Cohort 2 will consist of 4 male patients who will be 
randomized 3:1 to receive CM4620-IE plus supportive care versus supportive care alone. 
Planned doses for patients in both cohorts who are randomized to receive CM4620-IE are 1.0 
mg/kg on Day 1 and 1.4 mg/kg on Days 2-4. The first infusion of CM4620-IE must be started 
within 6 (up to 8) hours of the patient or LAR providing informed consent and should be 
administered IV over 4 hours. Subsequent infusions will be started every 24 hours (± 1 hour) 
from the start of the first infusion. 
The second phase will consist of 2 cohorts. Cohort 3 will consist of 8 female patients who will be 
randomized 3:1 to receive CM4620-IE plus supportive care versus supportive care alone. Cohort 
4 will consist of 8 male patients who will be randomized 3:1 to receive CM4620-IE plus 
supportive care versus supportive care alone. Planned doses for patients in both cohorts who are 
randomized to receive CM4620-IE are 2.08 mg/kg of CM4620-IE on Days 1 and 2, and 1.6 
mg/kg on Days 3 and 4. The first infusion of CM4620-IE must be started within 6 (up to 8) hours 
of the patient or LAR providing informed consent and will be administered intravenously IV 
over 4 hours. Subsequent infusions will be started every 24 hours (± 1 hour) from the start of the 
first infusion. 
The decision to start Cohort 3 will be made after CalciMedica reviews the available efficacy, 
safety and tolerability data from Cohort 1 and discusses with the Principal Investigators. The 
decision to start Cohort 4 in the second phase of the study will be made after CalciMedica 
reviews the available efficacy, safety and tolerability data from Cohort 2 and discusses with the 
Principal Investigators. 
For all 4 cohorts, a study physician or appropriately trained delegate will perform all assessments 
daily through Day 10, or until discharge if occurring earlier. After Day 10, and starting on Day 
12, serious adverse events (SAEs) will be captured every 48 hours until Day 30 (± 2 days), or 
until discharge if occurring earlier. Patients discharged prior to Day 30 will be contacted on Day 
30 (± 2 days) to capture SAEs and any re-admissions to the hospital. Patients will also be 
contacted on Day 90 (± 7 days) to assess mortality. 
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 cohort, the number of 
cohorts in each phase of the study, and/or the number of phases in the study for safety and/or 
efficacy considerations. 


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3.2 
End of Study 
The End of Study is considered the date on which the last patient randomized completes the visit 
on Day 90, unless CalciMedica or the Regulatory Authority overseeing this program terminates 
the study early. 
3.3 
Sponsor or Regulatory Agency Termination of the Study 
Although CalciMedica intends to complete the study as outlined, CalciMedica reserves the right 
to terminate the study at any time for any clinical or administrative reason, or if required by a 
regulatory agency. 
 
 


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4 
SELECTION OF PATIENTS 
4.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be randomized in a cohort: 
1. Diagnosis of acute pancreatitis established by the presence of abdominal pain consistent 
with acute pancreatitis and 1 of the following 2 criteria:  
a. Serum lipase or serum amylase > 3 times the upper limit of normal (ULN); 
b. Characteristic findings of acute pancreatitis on abdominal imaging; 
2. One of the following 2 criteria, either:  
a. A SpO2 <96% with a FiO2 of 21% (room air) to 27% or a SpO2 <97% with a FiO2 
≥28%; Or 
b. Diagnosis of SIRS, defined by the presence of at least 2 of the following 4 criteria: 
i. 
Temperature < 36°C or > 38°C; 
ii. 
Heart rate > 90 beats/minute; 
iii. 
Respiratory rate >20 breaths/minute or arterial carbon dioxide tension 
(PaCO2) <32 mmHg; 
iv. 
White blood cell count (WBC) >12,000 mm3, or <4,000 mm3, or > 10% 
immature (band) forms; 
3. No evidence of pancreatic necrosis on contrast-enhanced computed tomography (CECT) 
performed in the 18 hours prior to consent or after consent and before Day 1; 
4. Adults ≥ 18 years of age; 
5. A female patient of child bearing potential who is sexually active with a male partner 
must be willing to practice acceptable methods of birth control for 365 days after the last 
dose of CM4620-IE; 
6. A male patient who is sexually active with a female partner of childbearing potential 
must be willing to practice acceptable methods of birth control for 365 days after the last 
dose of CM4620-IE and must not donate sperm for 365 days; 
7. Willing and able to, or have a LAR that is willing and able to, provide informed consent 
to participate, and to cooperate with all aspects of the protocol. 
 
 


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4.2 
Exclusion Criteria 
Patients with any of the following conditions or characteristics must be excluded from enrolling 
in a cohort: 
1. Any concurrent clinical condition that a study physician believes could potentially pose 
an unacceptable health risk to the patient while involved in the study, including a CV 
SOFA score of 4 at the time of Screening, or may limit expected survival to <6 months: 
2. Suspected presence of cholangitis, in the judgment of the treating investigator; 
3. ERCP performed in the previous 7 days; 
4. Any malignancy being treated with chemotherapy or immunotherapy; 
5. Any autoimmune disease being treated with immunosuppressive medication or 
immunotherapy (Section 5.3 for list of prohibited medications); 
6. History of: 
a. Chronic pancreatitis, pancreatic necrosis or necrosectomy, or pancreatic enzyme 
replacement therapy; 
b. Biopsy proven cirrhosis, portal hypertension, hepatic failure/hepatic encephalopathy; 
c. Known hepatitis B or C, or HIV; 
d. History of organ or hematologic transplant; 
e. Resuscitated cardiac arrest, myocardial infarction, revascularization, cardiovascular 
accident (CVA) in the 30 days prior to Day 1; 
7. Current renal replacement therapy; 
8. Current known abuse of cocaine or methamphetamine; 
9. Known to be pregnant or are nursing; 
10. Participated in another study of an investigational drug or therapeutic medical device in 
the 30 days prior to Day 1; 
11. History of allergy to eggs or known hypersensitivity to any components of CM4620-IE. 
4.3 
Re-Screening 
A patient who fails screening because SIRS was not present, or SpO2 was ≥96% with a FiO2 of 
21% (room air) to 27% or SpO2 >97% with a FiO2 ≥28% during the initial screening, may be 
rescreened once within 18 hours of a CECT showing no necrosis. 


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5 
TREATMENT OF PATIENTS 
5.1 
Overview 
All patients in the study should receive supportive care consistent with the 2013 IAP/APA 
evidence-based guidelines for the management of acute pancreatitis, and local SOC for the 
management of other medical conditions. Other than at Screening, and all venous and arterial 
blood gas testing, the blood samples for laboratories collected as part of the protocol, will be 
tested at a central lab, and will not be available to assist the PI or treating physician in managing 
the patient. The PI or treating physician will order all laboratory testing necessary for the 
management of the patient and analysis of these samples will be performed at the local 
laboratory. 
Fluid resuscitation should be provided to all patients as recommended in the guidelines; lactated 
Ringer’s solution may be the preferred replacement fluid for patients with acute pancreatitis. 
Contrast Enhanced Computed Tomography (CECT) of the pancreas will be performed once on 
Day 5 through Day 7 in all patients. The CECTs performed as part of the protocol will read by a 
blinded central reader; scans will also be read locally and used by the PI or treating physician for 
patient management. 
A summary of recommendations from the 2013 IAP/APA evidence based guidelines for the 
management of acute pancreatitis is listed in Appendix 7. 
5.2 
Discharge Criteria 
The patient randomized to receive CM4620-IE should remain in the hospital until all 4 doses of 
CM4620-IE have been administered, and a CECT of the pancreas has been performed. The 
suggested criteria for discharging patients from the hospital are: 
• Abdominal pain has resolved 
• Normal oral diet is tolerated 
• There is no clinical or laboratory evidence of an infection 
If the patient is ready to be discharged before all 4 doses of CM4620-IE have been administered 
or the CECT of the pancreas has been performed, the PI or treating physician should contact the 
Medical Monitor prior to discharging the patient. 


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5.3 
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: abatacept, adalimumab, alemtuzumab, anakinra, basilizimab, 
belimumab, bevacizumab, brodalumab, canakinumab, certolizumab, cetuximab, 
daclizumab, eculizumab, etanercept, golimumab, infliximab, interferon, ixekizumab, 
muromonab, natalizumab, omalizumab, rituximab, secukinumab, tocilizumab, 
trastuzumab, ustekinumab, vedolizumab 
5.4 
Compliance 
Only the PI or his/her appropriately trained study staff will administer CM4620-IE to patients 
randomized in the trial in accordance with the protocol. CM4620-IE must not be used for any 
reasons other than that described in the protocol. 


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6 
PROCEDURES 
6.1 
Randomization Procedures 
Patients will be randomized 3:1 to receive CM4620-IE in addition to supportive care consistent 
with the 2013 IAP/APA evidence-based guidelines for the management of acute pancreatitis 
versus supportive care alone. Randomization will be stratified by sex. CalciMedica or its 
designee will prepare the randomization schedule prior to the start of the study. 
6.2 
Discontinuation and Withdrawal 
Discontinuation refers to the patient or PI discontinuing the administration of CM4620-IE before 
all 4 doses are administered despite the patient remaining in the hospital. Patients have the right 
to discontinue the administration of CM4620-IE at any time for any reason, without prejudice to 
their medical care. The PI may discontinue the administration of CM4620-IE because of an 
adverse event or change in medical status that raises a safety concern about the patient receiving 
additional doses of CM4620-IE. The PI must discontinue the administration of CM4620-IE if 
the patient is diagnosed with a new or recurrent malignancy, or if the patient was concomitantly 
administered a prohibited medication. If possible, the PI should contact the Medical Monitor to 
review the reasons for a patient’s discontinuation from study drug. The PI should also record the 
reason for the discontinuation in the eCRF and appropriate source documents at the site. Even if 
the patient discontinues receiving CM4620-IE, diligence should occur to ensure that all study 
visits and assessments are completed. 
Withdrawal refers only to the complete withdrawal of the patient from the study because of the 
withdrawal of consent. The PI should inform the Medical Monitor of the withdrawal of consent 
and record the withdrawal of consent in the eCRF and appropriate source documents at the site. 


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7 
CM4620-IE MATERIALS AND MANAGEMENT 
7.1 
CM4620-IE Product Description 
CM4620-IE 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 CM4620. CM4620-IE 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 CM4620 in aqueous solution. CM4620-IE 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 3) 
Table 3 
CM4620-IE Product Information 
Product Name: 
CM4620 Injectable Emulsion 
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. 
Manufacturer 
Bioserv Corporation 
San Diego, CA 92121 
 
7.2 
CM4620-IE Storage 
CM4620-IE 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 CM4620-IE does not 
freeze. Temperature logs should be maintained and available at each monitoring visit. When a 
temperature is noted outside the temporary excursion range of 2°C to 8°C 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 CM4620-IE has been demonstrated to 12 months and is being 
evaluated for longer periods in ongoing studies. 
7.3 
CM4620-IE Preparation 
The study pharmacist and/or designee will be responsible for the preparation and dispensation 
of CM4620-IE. Prior to administration, CM4620-IE must be transferred to a sterile container a 
using sterile technique. Specific details on how to calculate and prepare CM4620-IE, as well as 
the specific components that will be used to administer CM4620-IE, will be provided in a 
Pharmacy Manual. The Pharmacy Manual will also contain tables detailing the Volume to Be 


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Infused (VTBI) of CM4620-IE that is based upon the body weight of the patient, the selected 
dose level, and the concentration of CM4620-IE (1.6 mg/mL). 
7.4 
CM4620-IE Administration 
CM4620-IE will be administered intravenously over 4 hours at a constant rate of infusion. 
CM4620-IE shall be administered every 24 hours (± 1 hours) for a total of 4 doses. The dose of 
CM4620-IE that will be administered will be calculated using the patient weight obtained at 
Screening. A line into a peripheral or central vein may be used for the infusion. The peripheral 
IV should be 20 gauge in size or larger. The peripheral IV or central line port should be 
dedicated, i.e., only for the administration of CM4620-IE and 0.9% normal saline. CM4620-IE is 
compatible with 0.9% normal saline. The IV tubing used to administer CM4620-IE 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 flush the line to ensure that the VTBI is completely administered. If the 
administration of CM4620-IE is stopped because of a technical reason, such as failure of the IV 
site, or IV pump malfunction, the administration of CM4620-IE 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 CM4620-IE should be 
recorded. 
CalciMedica may modify at any time the administered doses of CM4620-IE, 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. If the 
administration of CM4620-IE is stopped because of a serious adverse event that is considered to 
be probably or definitely related to CM4620-IE, the Medical Monitor must be immediately 
contacted. 
7.5 
Packaging and Labeling 
Preparation, packaging and labeling of CM4620-IE 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. 
7.6 
Accountability, Handling and Disposal 
The PI or designee will ensure that deliveries of CM4620-IE from CalciMedica or its designee 
are received by a responsible person, and such deliveries are recorded; that CM4620-IE is 
handled and stored safely and properly; that CM4620-IE is only dispensed to study patients in 
accordance with the protocol; and that unused CM4620-IE 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 CM4620-IE. The 
pharmacy will maintain a record of CM4620-IE accountability. 


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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 onset of abdominal pain 
• Record the time of the patient or LAR provides informed consent 
After informed consent is obtained, the following procedures are to be performed: 
• Record demographics and medical history, including medication history 
• Record vital signs, height and weight 
• Perform a limited physical examination 
• Draw serum pregnancy test if the patient is a woman of child bearing potential – analyze 
at local lab 
o If already performed as part of standard of care, record results 
• Draw a blood sample for serum amylase and lipase–analyze at local lab; 
o If already performed at local lab as part of standard of care for the evaluation of 
abdominal pain, record results 
• Draw a blood sample for CBC, differential, and platelets–analyze at local lab 
o If already performed at local lab as part of standard of care for the evaluation of 
abdominal pain, record results 
• Determine if SIRS is present 
• Record the SpO2 and the FiO2 and time performed 
• In patients who have SIRS and a SpO2 <96% with a FiO2 of 21% (room air) to 27% or a 
SpO2 <97% with a FiO2 ≥28%, obtain a CECT of the pancreas, or review one performed 
as standard of care in the 18 hours prior to consent, to determine if pancreatic necrosis is 
present. The Screening CECT may have been performed more than 18 hours prior to 
consent and not repeated after consent for patients-specific safety considerations. 
If the patient satisfies all of the inclusion criteria and none of the exclusion criteria, immediately 
proceed to Day 1. 
8.2 
Day 1 (0 hour to < 24 hours) 
Perform the following procedures immediately prior to randomization of female patients into 
Cohort 1 (Cohort 3 during the second phase), and the randomization of male patients into 
Cohort 2 (Cohort 4 during the second phase): 
• Record vital signs 


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• Record concomitant medications 
• Draw a blood sample for CBC, differential and platelets, Chemistry Profile, serum 
biomarkers–send to central lab 
• Obtain a urine sample for biomarker testing–send to central lab 
• Record SpO2 and the FiO2 and time performed 
• If an ABG has already been performed as part of standard of care, record the pH, PaCO2, 
PaO2, SaO2 and the FiO2 at the time of draw 
• Calculate the Glasgow Coma Scale score  
• Record patient’s pain using the PNRS  
• Assess pain using the CPOT 
• Randomize patient 
If the patient has been randomized to receive CM4620-IE: 
• Start the administration of CM4620-IE (1st dose) as soon as possible after 
randomization and preferably within 6 hours (up to 8) from the time the patient or 
legal representative signed the informed consent; 
• If the administration of CM4620-IE is started more than 8 hours from the time the patient 
or legal representative provided informed consent, note the time and inform the Medical 
Monitor; 
• Draw a blood sample for PK 30 minutes (±15 minutes) after completing the 
administration of CM4620-IE-send to central lab 
• Draw a blood sample for PK 8 hours (±30 minutes) after completing the administration of 
CM4620-IE-send to central lab 
For all patients, at 12 hours (±1 hour) from time of randomization: 
• Record vital signs 
• Draw a blood sample for CBC, differential and platelets–send to central lab 
• Perform an AE/SAE assessment 
8.3 
Day 2 (24 hours to <48 hours) 
For all patients, at 24 hours (±1 hour) from time of randomization: 
• Record vital signs 
• Record concomitant medications 
• Draw a blood sample for CBC, differential and platelets, chemistry profile, serum 
biomarkers–send to central lab 


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• Obtain a urine sample for biomarkers–send to central lab 
• Record SpO2 and the FiO2 and time performed 
• Calculate the Glasgow Coma Scale Score 
• Record patient’s pain using the PNRS 
• Assess pain using the CPOT 
• Perform AE/SAE assessment 
For patients randomized to receive CM4620-IE: 
• Start the administration of CM4620-IE (2nd dose) 24 hours (± 1 hour) from the start 
of dose administration on Day 1 
o Draw a blood sample for PK 30 minutes (±15 minutes) prior to starting the 
administration of CM4620-IE-send to central lab 
For all patients, at 36 (±1 hour) hours from the time of randomization: 
• Record vital signs 
• Draw a blood sample for CBC, differential and platelets–send to central lab 
8.4 
Day 3 (48 hours to < 72 hours) 
For all patients, at 48 hours (±1 hour) from the time of randomization: 
• Record vital signs 
• Record concomitant medications 
• Draw a blood sample for CBC, differential and platelets, chemistry profile, serum 
biomarkers–send to central lab 
• Obtain a urine sample for biomarkers–send to central lab 
• Record SpO2 and the FiO2 and time performed 
• Calculate the Glasgow Coma Scale Score 
• Record patient’s pain using the PNRS 
• Assess pain using the CPOT 
• Perform AE/SAE assessment 
For patients randomized to receive CM4620-IE: 
• Start the administration of CM4620-IE (3rd dose) 48 hours (±1 hour) from the start 
of dose administration on Day 1 


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For all patients, at 60 hours (±1 hour) from the time of randomization: 
• Record vital signs 
• Draw a blood sample for CBC, differential and platelets–send to central lab 
8.5 
Day 4 (72 hours < 96 hours) 
For all patients, at 72 hours (±1 hour) from the time of randomization: 
• Record vital signs 
• Record concomitant medications 
• Draw a blood sample for CBC, differential and platelets, chemistry profile, 
serum biomarkers–send to central lab 
• Obtain a urine sample for biomarkers–send to central lab 
• Record SpO2 and the FiO2 and time performed 
• Calculate the Glasgow Coma Scale Score 
• Record patient’s pain using the PNRS 
• Assess pain using the CPOT 
• Perform AE/SAE assessment 
For patients randomized to receive CM4620-IE: 
• Start the administration of CM4620-IE (4th dose) 72 hours (±1 hour) from the start 
of dose administration on Day 1 
o Draw a blood sample for PK 30 minutes (± 15 minutes) after completing the 
administration of CM4620-IE-send to central lab 
o Draw a blood sample for PK 8 hours (± 30 minutes) after completing the 
administration of CM4620-IE-send to central lab 
For all patients, at 84 hours (±1 hour) from the time of randomization: 
• Record vital signs 
• Draw a blood sample for CBC, differential and platelets–send to central lab 
8.6 
Day 5 (96 hours to < 120 hours) 
For all patients, at 96 hours (±1 hour) from the time of randomization: 
• Record vital signs 
• Record concomitant medications 


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• Draw a blood sample for CBC, differential and platelets, chemistry profile, 
serum biomarkers–send to central lab 
• Obtain a urine sample for biomarkers–send to central lab 
• Record SpO2 and the FiO2 and time performed 
• Calculate the Glasgow Coma Scale Score 
• If an ABG has already been performed as part of standard of care, record the pH, PaCO2, 
PaO2, SaO2 and the FiO2 at the time of draw 
• Record patient’s pain using the PNRS 
• Assess pain using the CPOT 
• Perform AE/SAE assessment 
For patients randomized to receive CM4620-IE: 
• Draw a blood sample for PK at 96 hours (±1 hour) from the start of dose administration 
on Day 1-send to central lab 
For all patients, at 108 hours (±1 hour) from the time of randomization: 
• Record vital signs 
• Draw a blood sample for CBC, differential and platelets–send to central lab 
All patients will undergo a CECT of the pancreas on Day 5. 
• The CECT will be performed on Days 6 or 7 if unable to be performed on Day 5 
• If the PI wishes to discharge a patient randomized to supportive care only before Day 5, 
a CECT should be performed prior to discharge 
• If the PI wishes to delay the CECT beyond Day 7, the Medical Monitor should be 
contacted 
8.7 
Days 6 – 9 
For all patients who remain hospitalized, at 120 hours (±1 hour), 144 hours (±1 hour), 168 hours 
(±1 hour), 192 hours (±1 hour) from the time of randomization: 
• Record vital signs 
• Record concomitant medications 
• Draw a blood sample for CBC, differential and platelets, chemistry profile, serum 
biomarkers–send to central lab 
• Obtain a urine sample for biomarkers–send to central lab 
• Record SpO2 and the FiO2 and time performed 


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• Calculate the Glasgow Coma Scale Score 
• Record patient’s pain using the PNRS 
• Assess pain using the CPOT 
• Perform AE/SAE assessment 
8.8 
Day 10 
For all patients who remain hospitalized, at 216 hours (±1 hour) from the time of randomization: 
• Record vital signs 
• Record concomitant medications 
• Perform limited physical examination 
• Draw a blood sample for CBC, differential and platelets, chemistry profile, serum 
biomarkers–send to central lab 
• Obtain a urine sample for biomarkers–send to central lab 
• Record SpO2 and the FiO2 and time performed 
• Calculate the Glasgow Coma Scale Score 
• If an ABG has already been performed as part of standard of care, record the pH, PaCO2, 
PaO2, SaO2 and the FiO2 at the time of draw 
• Record patient’s pain using the PNRS 
• Assess pain using the CPOT 
• Perform AE/SAE assessment 
For patients randomized to receive CM4620-IE: 
• Draw a blood sample for PK at 216 hours (±1 hour) from the start of dose administration 
on Day 1-send to central lab 
If the patient is discharged after Day 5 and before Day 10, Day 10 procedures should be 
performed prior to discharge. 
8.9 
Days 12 – 30 
For all patients who remain hospitalized: 
• Perform AE/SAE assessment if the patient is in the hospital every 48 hours starting on 
Day 12 until discharge, or until Day 30 


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• If the patient has been discharged from the hospital, contact the patient on Day 30 
(± 2 days) for SAE assessment and to determine if patient has been readmitted to the 
hospital (may be conducted by phone call to patient, LAR, primary MD, or chart review) 
8.10 
Day 90 
For all patients: 
• On Day 90 (± 7 days), conduct a mortality assessment (may be completed by phone call 
to patient, LAR, primary MD, or chart review) 
8.11 
Study Assessments 
8.11.1 
Medical History 
To the extent possible given the patient’s medical condition, a complete medical history will be 
collected at Screening. Demographic data will be collected as the initial part of the medical 
history. Patients must be specifically questioned for whether they have had previous episodes of 
acute pancreatitis and whether they have been given a diagnosis of chronic pancreatitis. A family 
history of either acute or chronic pancreatitis will be obtained. Smoking and alcohol history will 
be noted as part of the social history. Medications that were being taken prior to enrollment in 
the study will be collected as part of the medical history as will, if available, baseline 
laboratories. 
8.11.2 
Concomitant Medications 
Concomitant medications will be recorded from Day 1 through Day 10, or until discharge, 
whichever comes first. The name, dose and frequency of all medications that the patients are 
taking will be recorded, including vasopressor(s) and highest dose of vasopressors. Pain 
medications and anti-pyretic medications, the time of administration of the individual doses, and 
the route of administration will also be recorded. Generic names should be used when possible. 
8.11.3 
Physical Examination 
A limited physical examination will be performed and recorded at Screening and Day 10, or at 
discharge if occurring earlier. The physical examination will evaluate the following systems: 
cardiovascular, respiratory, gastrointestinal, musculoskeletal, and skin. The examination must 
specifically assess if the patient has abdominal guarding or rebound tenderness. 
8.11.4 
Glasgow Coma Scale Score 
A Glasgow coma scale score will be determined at Day 1 and on Days 2 – 10. If possible, the 
Glasgow coma scale score should be determined prior to administration of sedatives. Patients 
should also be free from the effects of paralysis or neuromuscular blocking agents. If the patient 


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is sedated or paralyzed and the Glasgow coma scale is unable to be performed, please leave 
blank in the eCRF. The Glasgow coma scale score may be determined using the table below: 
Table 4 
Glasgow Coma Scale Score 
 
Score 
Eye Opening 
 
Spontaneous 
4 
Response to verbal command 
3 
Response to pain 
2 
No eye opening 
1 
Best Verbal Response 
 
Oriented 
5 
Confused 
4 
Inappropriate words 
3 
Incomprehensible sounds 
2 
No verbal response 
1 
Best Motor Response 
 
Obeys commands 
6 
Localizing response to pain 
5 
Withdrawal to pain 
4 
Flexion to pain 
3 
Extension to pain 
2 
No motor response 
1 
Total Score 
________ 
8.11.5 
Vital Signs 
The recorded vital signs must include the patient’s current temperature, heart rate (beats per 
minute), systolic and diastolic blood pressures, respiratory rate (breaths per minute), and the total 
input and output of fluids. The highest and lowest temperatures, the highest heart rate, and the 
highest respiratory rate since the prior study-required assessment will also be recorded. The total 
input of fluids (oral and intravenous) and the total output of fluids (urine output and nasogastric 
output) since the prior study-required assessment will be recorded.  
If the patient has been started on vasopressor therapy since the prior study-required assessment, 
the start time should be recorded. If the patient has been placed on renal replacement therapy 
since the prior study-required assessment, the type of therapy will be recorded. If the patient has 
been placed on mechanical ventilation since the prior study-required assessment, the type of 
ventilation will be recorded (noninvasive or invasive mechanical ventilation). The current 
settings for fraction of inspired oxygen (FiO2), respiratory rate, tidal volume and positive end-
expiratory pressure (PEEP) at the assessment will be recorded. If intra-abdominal pressures are 
being monitored, the current pressure and the highest pressure since the prior study-required 
assessment should be recorded. All solid food intake since the prior study-required assessment 
will be recorded including the time and date of the meal, the percent of the meal completed, if 
there were nausea or vomiting with the meal, and if pain medications had to be given one hour 
prior to or after the meal to treat symptoms due to ingesting the meal. 


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8.11.6 
Arterial Blood Gas 
If an arterial blood gas (ABG) has already been performed as part of supportive care on Days 1, 
5 and 10 the pH, PaO2, PaCO2, SaO2 and FiO2 will be recorded. 
8.11.7 
Pulse Oximetry 
A pulse oximetry measurement of oxygen saturation, (SpO2), will be measured at Screening and 
on Days 1 – 10. The PI or appropriately trained study coordinator will review the pulse oximetry 
waveform to attest to its adequacy. The FiO2 at the time of the pulse oximetry 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 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 table below allows for the conversion of oxygen flow in L/min 
to 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 EPICII 
 
8.11.8 
Pregnancy Testing 
A serum pregnancy test must be performed for all women of childbearing potential from a blood 
sample collected at Screening. The result of the test must be negative for the patient to be 
randomized and receive CM4620-IE. 


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8.11.9 
Laboratory Analyses 
At Screening, an amylase or lipase, CBC, differential, and platelets, will be performed at the 
local lab. The results of the CBC will be used to determine the presence of SIRS. On Days 1 – 5, 
a CBC, differential, and platelet count will be drawn twice, and chemistry profile will be drawn 
once, and sent to the central lab. On Days 6 – 10, a CBC, differential, platelet count, and 
chemistry profile will be collected once and sent to the central lab. The chemistry profile sent to 
the central lab will consist of sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, glucose, calcium, total protein, globulin, albumin, alkaline phosphatase, alanine 
transaminase (ALT), aspartate transaminase (AST), total bilirubin, lactate dehydrogenase (LDH), 
total cholesterol and triglycerides. The results from these laboratory samples will not be available 
to the PI or treating physician for the management of the patient with acute pancreatitis. 
The PI or treating physician will order all laboratory testing necessary for the management of the 
patient and analysis will be performed at the local laboratory. Other than at Screening, and all 
venous and arterial blood gas testing, the blood samples for laboratories ordered as part of the 
protocol, will be tested at a central lab, and will not be available to assist the PI or treating 
physician in managing the patient. 
8.11.10 
PK analysis 
On Day 1, a PK sample will be obtained 30 minutes after and 8 hours after completing the 
administration of CM4620-IE; if necessary the 8 hour sample may be obtained at 12 hours 
together with the 12-hour hematology blood draw. On Day 2 a PK sample will be obtained 
30 minutes prior to starting the administration of CM4620-IE. On Day 4 a PK sample will be 
obtained 30 minutes after and 8 hours after completing the administration of CM4620-IE if 
necessary the 8 hour sample may be obtained at 84 hours together with the 84-hour hematology 
blood draw. A PK sample will be drawn on Day 5, and in those patients who remain in the 
hospital, on Day 10. The date and time of the PK blood sample (both the absolute time and the 
time before or after administration of CM4620-IE) should be recorded. All PK samples will be 
sent to the central lab. 
8.11.11 
Biomarker Analysis 
For biomarker testing, serum and urine samples will be collected on Days 1 – 10 and sent to the 
central lab. The date and time of the blood and urine samples should be recorded. Serum 
biomarkers planed for testing include C-Reactive Protein (CRP), D-Dimer, procalcitonin, Il-6 
and Il-8. Urine NGAL will also be tested. Results will not be provided to the PI or treating 
physician. 
8.11.12 
Numeric Pain Rating Scale (PNRS) 
In patients who are able to self-report their pain, the Pain Numeric Rating Scale (Appendix 8) 
will be used to grade the severity of the abdominal pain from Day 1 – 10, or until discharge if 
occurring earlier. The timing of the last dose of an analgesic prior to assessing the patient’s pain 


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should also be recorded. The characteristic of the pain and the similarity to the presenting pain 
will also be recorded. 
8.11.13 
Critical-Care Pain Observation Tool 
The Critical-Care Pain Observation Tool (CPOT) will be employed by the PI or study designee 
to assess the patient’s pain from Day 1 – 10, or until discharge if occurring earlier. The patient 
must be observed for one minute at rest. The timing of the last dose of an analgesic prior to 
assessing the patient’s pain should be recorded. The sum of the scores for facial expression, body 
movements, compliance with ventilator, or vocalization if extubated, and muscle tension will be 
determined using the CPOT (Appendix 9). 
8.11.14 
Contrast-Enhanced Computed Tomography (CECT) of the Pancreas 
All patients will undergo a CECT of the pancreas at Screening, and on Day 5. The Screening 
CECT may have been performed more than 18 hours prior to consent and not repeated after 
consent for patients-specific safety considerations. The Day 5 CECT will be performed on Days 
6 or 7 if unable to be performed on Day 5. The CECT will be performed prior to discharge if 
discharge is planned sooner than Day 5. 
The recommended CECT protocol: 
• 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 
The CECT protocol may be altered to local standard of care. If the patient has acute kidney 
injury or renal failure, the CECT may be done at the discretion of the local radiologist, treating 
physician or PI without the non-ionic contrast bolus or with a lower amount of non-ionic 
contrast. The PI or treating physician may also elect to change the timing of the Day 5 CECT due 
to patient-specific safety considerations to later than Day 7, 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. 
Patients with a history of acute pancreatitis who have SIRS or a SpO2 <96% with a FiO2 of 21% 
(room air) to 27% or SpO2 <97% with a FiO2 ≥28% at Screening must have no evidence of 
pancreatic necrosis by CECT performed in the 18 hours prior to consent or after consent and 
before Day 1. The Screening CECT may have been performed more than 18 hours prior to 
consent and not repeated after consent for patients-specific safety considerations. 


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The Day 5 CECT and the CECT performed at screening will 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, the 
date of the CECT and the results of the CECT as read by the local radiologist will be recorded. 
Image results from the additional CECTs will also be captured. 
8.11.15 
Systemic Inflammatory Response Syndrome (SIRS) 
The physician, or appropriately trained designee will determine the presence of SIRS at 
Screening. 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 CM4620-IE, whether or not it is considered related to CM4620-IE 
administration. Included in this definition is any newly occurring event or previous condition that 
has increased in severity or frequency since the administration of CM4620-IE. 
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 CM4620-IE 
• Is an important medical event 
The term “life-threatening” refers to an event in which the patient was at immediate risk of death 
at the time of the event. It does not refer to an event that hypothetically might have caused death 
if it were more severe. 
Important medical events are those that may not need any of the criteria defined above; however, 
they may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the SAE definition. 
Pregnancy is not considered an AE; however, information will be collected for any pregnancies 
that occur during CM4620-IE administration or the thirty days thereafter. Certain pregnancy 
outcomes will require submission as an SAE.  


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9.3 
Eliciting Adverse Event Information 
At every AE/SAE assessment, the patient must be asked a standard, non-directed question, such 
as, “how have you been feeling since your last visit?” to elicit any medically related changes in 
their well-being. In addition, the hospital chart and other documents relevant to patient safety 
must be reviewed when the patient is in the hospital. 
9.4 
Recording Adverse Events 
Recording of AEs must begin after randomization. All conditions present before randomization, 
including untoward medical events during Screening, should be documented as medical history. 
Documentation shall continue until the patient dies, the patient withdraws consent, or the 
patient’s participation in the study ends. Information to be collected includes: 
• Type of event 
• Date of onset 
• Date of resolution 
• Investigator-specified relationship to CM4620-IE and assessment of severity 
• Seriousness 
• Any action taken 
While an AE is ongoing, changes in the severity (e.g., worsening and improving) should be 
noted in the source documents, but when documenting the AE, only the total duration and the 
greatest severity should be recorded in the case report form. AEs characterized as intermittent 
require documentation of onset and duration. 
All AEs reported or observed during the study must be followed to resolution. Or, if not fully 
resolved, until the condition has stabilized, the patient dies, withdraws consent, or CalciMedica 
ends the trial whichever is first. 
Adverse events resulting from concurrent illnesses, reactions to concurrent medications, or 
progression of disease states must also be reported. Pre-existing conditions (present before the 
start of the AE collection period) are considered concurrent medical conditions and should NOT 
be recorded as AEs. However, if the patient experiences a worsening or complication of such a 
concurrent condition, the worsening or complication should be recorded as an AE. Investigators 
should ensure that the AE term recorded captures the change in condition (e.g., “worsening of…”). 
Each AE should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory test values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded as an AE(s). 
Elective procedures (surgeries or therapies) performed to manage/treat conditions that existed 
prior to the patient enrolling in the trial should not be recorded as AEs but should be documented 
in the patient’s source documents. If a planned procedure is performed early (e.g., as an 
emergency) because the pre-existing condition worsens, the worsening condition should be 
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9.5 
Assessment of Relationship to CM4620-IE 
The Investigator must use the following classification and criteria to characterize the relationship 
or association of CM4620-IE in causing or contributing to the AE: 
• Unrelated: This relationship suggests that there is no association between CM4620-IE 
and the reported event 
• Unlikely: This relationship suggests that there is an unlikely association between 
CM4620-IE and the reported event 
• Possible: This relationship suggests that treatment with CM4620-IE caused or 
contributed to the AE. That is, the event follows a reasonable temporal sequence from the 
time of CM4620-IE administration, and/or follows a known response pattern to the 
CM4620-IE, but could have been produced by other factors 
• Probable: This relationship suggests that a reasonable temporal sequence of the event 
with CM4620-IE administration exists and, based upon the known pharmacological 
action of the drug, known or previously reported adverse reactions to the drug or class of 
drugs, or judgment based on the Investigator’s clinical experience, the association of the 
event with CM4620-IE administration seems likely 
• Definite: This relationship suggests a definite causal relationship exists between 
CM4620-IE administration and the AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not appear 
to explain the event 
9.6 
Assessment of Severity 
The Investigator must use the following criteria to rate the intensity of the AE: 
• Mild: Symptoms causing no or minimal interference with usual social and functional 
activities 
• Moderate: Symptoms causing greater than minimal interference with usual social and 
functional activities 
• Severe: Symptoms causing inability to perform usual social and functional activities 
 
 


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9.7 
Reporting of Serious Adverse Events 
The Investigator is responsible for reporting to CalciMedica or designee within 24 hours from 
the time when site personnel learn about the event all SAEs that are observed or reported by the 
patient during the study (from randomization until the patient dies, the patient withdraws 
consent, or the patient’s participation in the study ends) regardless of the relationship to 
CM4620-IE 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.  
CalciMedica or its designee will notify the regulatory authority of any fatal or life threatening 
unexpected related events associated with the use of CM4620-IE 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. For SAEs that do not meet the fatal or 
life threatening unexpected related criteria, CalciMedica or its designee will notify the 
appropriate regulatory agencies in writing within fifteen calendar days. 
CalciMedica or its designee will provide copies of any reports to regulatory agencies regarding 
unexpected SAEs to the Investigators for review and submission to the institutional review board 
(IRB), Ethics Committee (EC) or Research Ethics Board (REB). The PIs are responsible for 
informing their IRB, EC, or REB of any SAEs at their site. SAE correspondence with regulatory 
authorities, IRBs, ECs or REBS must be submitted to CalciMedica or its designee for filing. 
In addition, the following adverse events that are commonly observed in this patient population 
will not be reported to the regulatory authority as individual expedited reports except in unusual 
circumstances: 
• Hypoxemia and acute respiratory distress syndrome 
• Oliguria and acute kidney injury 
• Hypotension and shock 
• Bacteremia 
• Pneumonia 
• Obtundation 
• Splanchnic venous thrombosis 
• Abdominal compartment syndrome 
• Gastroparesis and ileus 
• Local complications of the pancreas and peripancreatic tissue 
• Endoscopic retrograde cholangiopancreatography 
• Abdominal surgery including but not limited to cholecystectomy, pancreatic 
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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 CM4620-IE and is sexually active with a 
male partner, and a male patient who receives CM4620-IE 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 
365 days after last dose of CM4620-IE. 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 365 days after last dose of CM4620-IE. If the female 
patient is receiving CM4620-IE when discovered to be pregnant, the CM4620-IE 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. 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 ANALYSIS 
10.1 
Sample Size 
This open-label study will enroll 24 patients. The sample size was selected based on practical 
considerations to initially evaluate the safety, efficacy and pharmacokinetic profile of CM4620-IE 
in patients with acute pancreatitis and accompanying SIRS or Hypoxemia. This study is not 
powered for analysis of study data with inferential statistics. 
10.2 
Study Assessments 
• Safety assessments will include physical examinations, vital sign measurements, clinical 
laboratory measurements, concomitant medications and incidence, intensity and 
relationship of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) 
• Efficacy assessments will include SIRS score, APACHE II score, CECT of the pancreas, 
Organ Failure score, Sequential Organ Failure Assessment (SOFA) score, biomarker 
measurements including, but not limited to, C-Reactive Protein (CRP), D-Dimer, 
procalcitonin, urine NGAL, Il-6 and Il-8, Pain Numeric Rating Scale (PNRS) score and 
Critical-Care Pain Observation Tool (CPOT) score 
• Pharmacokinetic assessment will include CM4620 concentration-time data and selected 
pharmacokinetic parameters including maximum plasma concentration 
10.3 
Analysis Sets 
• The full analysis set includes all patients with acute pancreatitis who are randomized who 
receive at least one administration of CM4620-IE 
• The per protocol population includes all patients with acute pancreatitis who are 
randomized and have no major protocol violations leading to exclusion from the study 
• The safety population includes all patients who receive any amount of study drug 
treatment 
 
 


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10.4 
Statistical Analyses Plan 
A Statistical Analysis Plan (SAP) detailing the analyses for the study will be developed prior to 
the database lock. The SAP will serve as the final arbiter of all statistical analyses. Data will be 
summarized using descriptive statistics only. Continuous data will be summarized with number 
of patients (n), mean, median, minimum, maximum, standard of deviation, coefficient of 
variation and or geometric mean. Categorical data will be summarized with number and 
proportion of patients. The number of patients randomized in the study and the number of 
patients completing assessments for each Day will be summarized by cohort, sex and treatment 
arm. The number of patients and reasons for discontinuation of CM4620-IE or withdrawal from 
the study will be summarized. 
Efficacy endpoints that will be analyzed will include, but not limited to, SIRS score, APACHE II 
score, CT severity index scores, classification indexes, organ failure scores, SOFA score, 
biomarker values and pain scores. These endpoints will be further detailed in the SAP. 


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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 the study site periodically and maintain necessary telephone 
and letter contact with the PI and his/her study staff. The site monitor will maintain current 
knowledge of each site’s study activity by observing the conduct of the study at the site, 
reviewing study records and source documentation, 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/REB) reviews, and regulatory inspections. In the 
event of an audit, the PI agrees to allow CalciMedica or its representatives and relevant 
regulatory authorities access to all study records. 
If any regulatory agency schedules an audit, the PI should promptly notify CalciMedica or its 
representatives and promptly forward to CalciMedica copies of any audit reports he/she receives. 
11.4 
Study Record Retention 
The PI or his/her study staff must retain essential documents for at least 2 years after the last 
approval of a marketing application in an ICH region. They should retain these documents longer 
if required because of regulatory requirements or because of an agreement with CalciMedica. 
11.5 
Study Conduct: Good Clinical Practice and Declaration of Helsinki 
CalciMedica will design the clinical study, shall implement it, and report it in accordance with 
the ICH Harmonized Guideline for Good Clinical Practice, with applicable local regulations 
(e.g., European Directive 2001/83/EC and US Code of Federal Regulations Title 21), and with 
the ethical principles laid down in the Declaration of Helsinki. 
The PI agrees to conduct the study in accordance with the ICH Guideline for Good Clinical 
Practice, with applicable local regulations (e.g., European Directive 2001/83/EC and US Code of 
Federal Regulations Title 21) and with the principles of the Declaration of Helsinki. The PI must 
conduct all aspects of this study in accordance with all national, state and local laws or 
regulations. 


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11.6 
Responsibilities of the Investigator and the IRB/EC/REB 
A properly constituted IRB/EC/REB 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/REB 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/REB chairperson or designee must sign all IRB/EC/REB approvals and must 
identify the IRB/EC/REB 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/REB. The specified intervals should not exceed 1 year. The PI must supply CalciMedica 
or its designee written documentation of the reviews of the clinical research. 
11.7 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality. All records will be kept in a secure storage 
area with limited access. Clinical information will not be released without the written permission 
of the patient (or the patient’s legal representative) except as necessary for monitoring and 
auditing by CalciMedica or its designee, inspections by relevant regulatory authorities, or 
reviews by the IRB/EC/REB. 
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/REB approval or notification. Only after approval by CalciMedica, the PI, the 
IRB/EC/REB, 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/REB and regulatory 
authorities. 
The revision number and date of the amendment will be recorded on the title page of the 
protocol. 


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The PI is responsible for informing the IRB/EC/REB 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. 
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 (1R) and the principles of the Declaration of Helsinki. 
CalciMedica or it 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/REB. After CalciMedica or its designee 
review the informed consent form, the PI or his/her study staff will submit it to the IRB/EC/REB 
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/REB. The study staff must provide CalciMedica or its designee a copy of the 
revised informed consent form after IRB/EC/REB approves it. All patients or LARs affected by 
the revision must sign the revised informed consent form after the IRB/EC/REB 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/REB 
approved informed consent form. A LAR of the patient may provide informed consent on behalf 
of the patient under conditions authorized by local laws and regulations. The patient or LAR 
must provide informed consent before the patient undergoes any study-specific procedures 
described in the protocol. The PI or designee will provide a copy of the informed consent form to 
the patient and/or LAR. The process of obtaining informed consent must also be documented in 
the patient source documents. 
11.10 Protocol Violations and Deviations 
The PI or designee must document any protocol deviation or violation. Reporting of protocol 
deviations and violations to the appropriate IRB/EC/REB is the responsibility of the PI and must 
follow the applicable IRB/EC/REB guidelines. 


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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/REB but must notify CalciMedica or 
its designee and IRB/EC/REB 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 
financially responsible for the treatment of the patient’s underlying disease. 
11.13 Investigator Documentation 
Before beginning the study, the PI will be asked to comply with ICH E6 (R2) 8.2 and title 21 
CFR by providing to CalciMedica or designee the following documents: 
• An original signed investigator agreement page of the protocol 
• The IRB/EC/REB approval of the protocol 
• The IRB/EC/REB approved informed consent form 
• Any written information regarding the study that will be provided to the patient or LAR 
• A Form FDA 1572, fully executed, and all updates on new fully executed Form FDA 
1572 (Unless granted an exemption by the FDA and in compliance with local 
regulations) 
• Curricula Vitae for the PI and each sub-Investigator listed on Form FDA 1572. Evidence 
of licensure must be noted on the Curricula Vitae or a copy of the license must be 
provided. The Curricula Vitae must have been signed and dated by the PI and sub-
Investigators within 2 years before study start-up to indicate that the documents are 
accurate and current 
• Completed financial disclosure forms to allow CalciMedica or designee to submit 
complete and accurate certification or disclosure statements required under US Title 21 
CFR 54. In addition, the PI and sub-Investigators must provide to CalciMedica or 
designee a commitment to update this information promptly if any relevant changes occur 
during the course of the study and for 1 year following completion of the study 
• Laboratory certifications and normal ranges for any laboratories used by the site for the 
conduct of the study 


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11.14 Clinical Study Insurance 
CalciMedica has subscribed to an insurance policy, covering in its terms and provisions its legal 
liability for injuries caused to participating persons and arising out of this research that is 
performed strictly in accordance with the scientific protocol as well as with applicable law and 
professional standards. 
11.15 Use of Information 
All information supplied by CalciMedica to the PI and his/her study staff is privileged and 
confidential. The PI and his/her study staff agree to use this information to accomplish the study 
and not to use it for other purposes without consent from CalciMedica. Furthermore, the PI and 
his/her study staff is 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 
CM4620-IE, 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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12 
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Radiology. 2002;223(3):603-13. doi: 10.1148/radiol.2233010680. 
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. 
doi: 10.1136/gutjnl-2012-302779. 
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 
therapy? Cell Calcium. 2016;60(3):180-9. doi: 10.1016/j.ceca.2016.04.007. 
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, 
Education A. Determinant-based classification of acute pancreatitis severity: an international 
multidisciplinary consultation. Ann Surg. 2012;256(6):875-80. 
doi: 10.1097/SLA.0b013e318256f778. 
Gélinas C, Fillion L, Puntillo KA, Viens C, Fortier M. Validation of the critical-care pain 
observation tool in adult patients. Am J Crit Care. 2006;15(4):420-7. 
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. doi: 
10.1073/pnas.1300910110. 
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease 
classification system. Crit Care Med. 1985;13(10):818-29. 
Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet. 2015;386(9988):85-96. 
doi: 10.1016/S0140-6736(14)60649-8. 
Lindkvist B, Appelros S, Manjer J, Berglund G, Borgstrom A. A prospective cohort study of 
smoking in acute pancreatitis. Pancreatology. 2008;8(1):63-70. doi: 10.1159/000114868. 
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 
STIM1 from IP(3) receptors. Curr Biol. 2009;19(19):1648-53. doi: 10.1016/j.cub.2009.07.072. 
Mortele KJ, Wiesner W, Intriere L, Shankar S, Zou KH, Kalantari BN, Perez A, vanSonnenberg 
E, Ros PR, Banks PA, Silverman SG. A modified CT severity index for evaluating acute 
pancreatitis: improved correlation with patient outcome. AJR Am J Roentgenol. 
2004;183(5):1261-5. doi: 10.2214/ajr.183.5.1831261. 


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Muallem S, Schoeffield MS, Fimmel CJ, Pandol SJ. Agonist-sensitive calcium pool in the 
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Petersen OH, Sutton R. Ca2+ signalling and pancreatitis: effects of alcohol, bile and coffee. 
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Petersen OH, Gerasimenko OV, Gerasimenko JV. Pathobiology of acute pancreatitis: focus on 
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Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, 
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Appendix 1 
Definition of Organ Failure 
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, or 
• SpO2/FiO2 ≤315, or 
• The use of noninvasive or invasive mechanical ventilation 
For the renal system, in patients without known chronic kidney disease, organ failure will be 
defined as: 
• An increase in serum creatinine ≥300% if the baseline creatinine is known from prior to 
the hospitalization for acute pancreatitis, or  
• A serum creatinine ≥1.9 mg/dL, or 
• Urine output of <0.3 mL/kg/hour for ≥24 hours or anuria for ≥12 hours, or 
• 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: 
• An increase in serum creatinine ≥300% if the baseline creatinine is known from prior to 
the hospitalization for acute pancreatitis, or 
• An increase of serum creatinine to a level >4.0 mg/dl, or 
• Urine output of <0.3 mL/kg/hour for ≥24 hours or anuria for ≥12 hours, 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 
The presence of organ failure will be assessed on Days 1-10. 


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Appendix 2 
Sequential Organ Failure Assessment (SOFA) 
A Sequential Assessment Organ Failure (SOFA) Score will be calculated on Days 1-10. On Days 
1-10, it will be calculated using the Glasgow Coma Scale score and laboratory values assessed at 
the central laboratory and SpO2/FiO2 collected at the start of the Day. The PaO2/FiO2 used in the 
SOFA score calculation will be estimated from the SpO2/FiO2 
 
Adapted from Singer 2016 


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Appendix 3 
CTSI Score 
Balthazar 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 
Modified CTSI Score 
Pancreatic Inflammation 
Points 
Normal Pancreas 
0 
Intrinsic pancreatic abnormalities with or without inflammatory changes in the 
peripancreatic fat 
2 
Pancreatic or peripancreatic fluid collection or peripancreatic fat necrosis 
4 
Pancreatic Necrosis 
 
None 
0 
≤30% 
2 
>30% 
4 
Extra-pancreatic Complications 
 
One or more of pleural effusion, ascites, vascular complications, parenchymal 
complications or gastrointestinal tract involvement) 
2 
Adapted from Mortele 2004 
 
Total points are the sum of the points for pancreatic inflammation, pancreatic necrosis and extra-
pancreatic complications: 
• 0-2: mild acute pancreatitis 
• 4-6: moderate acute pancreatitis 
• 7-10: severe acute pancreatitis 


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Appendix 5 
Revised Atlanta Classification of Acute Pancreatitis 
Grades of Severity 
Mild 
No organ failure 
No local or systemic complications 
Moderately Severe 
Organ failure that resolves within 48 hours and/or 
Local or systemic complications without organ failure 
Severe 
Persistent Organ Failure 
Adapted from Banks 2013 


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Appendix 6 
Determinant Based Classification of Acute Pancreatitis 
Severity (DBCAPS) 
 
Mild AP 
Moderate AP 
Severe AP 
Critical AP 
(Peri)pancreatic necrosis 
No 
Sterile 
Infected 
Infected 
 
And 
And/Or 
Or 
And 
Organ Failure 
No 
Transient 
Persistent 
Persistent 
Adapted from Dellinger 2011 
 
 


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Appendix 7 
IAP/APA Summary of Recommendations 
A. Diagnosis of Acute Pancreatitis and Etiology 
1. The definition of acute pancreatitis is based on the fulfillment of 2 out of 3 of the following 
criteria: clinical (upper abdominal pain), laboratory (serum amylase or lipase >3x upper limit of 
normal) and/or imaging (CT, MRI, ultrasonography) criteria. (GRADE 1B, strong agreement) 
2. On admission, the etiology of acute pancreatitis should be determined using detailed 
personal (i.e. previous acute pancreatitis, known gallstone disease, alcohol intake, medication 
and drug intake, known hyperlipidemia, trauma, recent invasive procedures such as ERCP) and 
family history of pancreatic disease, physical examination, laboratory serum tests (i.e. liver 
enzymes, calcium, triglycerides), and imaging (i.e. right upper quadrant ultrasonography). 
(GRADE 1B, strong agreement) 
3. In patients considered to have idiopathic acute pancreatitis, after negative routine work-up 
for biliary etiology, endoscopic ultrasonography (EUS) is recommended as the first step to 
assess for occult microlithiasis, neoplasms and chronic pancreatitis. If EUS is negative, 
(secretin-stimulated) MRCP is advised as a second step to identify rare morphologic 
abnormalities. CT of the abdomen should be performed. If etiology remains unidentified, 
especially after a second attack of idiopathic pancreatitis, genetic counseling (not necessarily 
genetic testing) should be considered. (GRADE 2C, weak agreement) 
B. Prognostication/Prediction of Severity 
4. Systemic inflammatory response syndrome (SIRS) is advised to predict severe acute 
pancreatitis at admission and persistent SIRS at 48 hours. (GRADE 2B, weak agreement) 
5. During admission, a 3-dimension approach is advised to predict outcome of acute 
pancreatitis combining host risk factors (e.g. age, co-morbidity, body mass index), clinical risk 
stratification (e.g. persistent SIRS) and monitoring response to initial therapy (e.g. persistent 
SIRS, blood urea nitrogen, creatinine). (GRADE 2B, strong agreement) 
C. Imaging 
6. The indication for initial CT assessment in acute pancreatitis can be: 1) diagnostic 
uncertainty, 2) confirmation of severity based on clinical predictors of severe acute pancreatitis, 
or 3) failure to respond to conservative treatment or in the setting of clinical deterioration. 
Optimal timing for initial CT assessment is at least 72-96 hours after onset of symptoms. 
(GRADE 1C, strong agreement) 
7. Follow up CT or MR in acute pancreatitis is indicated when there is a lack of clinical 
improvement, clinical deterioration, or especially when invasive intervention is considered. 
(GRADE 1C, strong agreement) 
8. It is recommended to perform multi-detector CT with thin collimation and slice thickness 
(i.e. 5mm or less), 100-150 ml of non-ionic intra-venous contrast material at a rate of 3mL/s, 
during the pancreatic and/or portal venous phase (i.e. 50-70 seconds delay). During follow up 
only a portal venous phase (monophasic) is generally sufficient. For MR, the recommendation 


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is to perform axial FS-T2 and FS-T1 scanning before and after intravenous gadolinium contrast 
administration. (GRADE 1C, strong agreement) 
D. Fluid Therapy 
9. Ringer’s lactate is recommended for initial fluid resuscitation in acute pancreatitis. (GRADE 
1B, strong agreement) 
10a. Goal directed intravenous fluid therapy with 5-10 ml/kg/h should be used initially until 
resuscitation goals (see Q10b) are reached. (GRADE 1B, weak agreement) 
10b. The preferred approach to assessing the response to fluid resuscitation should be based on 
one or more of the following: 1) non-invasive clinical targets of heart rate <120/min, mean 
arterial pressure between 65-85 mmHg (8.7-11.3 kPa), and urinary output > 0.5e1ml/kg/h, 2) 
invasive clinical targets of stroke volume variation, and intra-thoracic blood volume 
determination, and 3) biochemical targets of hematocrit 35-44%. (GRADE 2B, weak 
agreement) 
E. Intensive Care Management 
11. Patients diagnosed with acute pancreatitis and one or more of the parameters identified at 
admission as defined by the guidelines of the Society of Critical Care Medicine (SCCM). 
Furthermore, patients with severe acute pancreatitis as defined by the revised Atlanta 
Classification (i.e. persistent organ failure) should be treated in an intensive care setting. 
(GRADE 1C, strong agreement) 
12. Management in, or referral to, a specialist center is necessary for patients with severe acute 
pancreatitis and for those who may need interventional radiologic, endoscopic, or surgical 
intervention. (GRADE 1C, strong agreement) 
13. A specialist center in the management of acute pancreatitis is defined as a high- volume 
center with up-to-date intensive care facilities including options for organ replacement therapy, 
and with daily (i.e. 7 days per week) access to interventional radiology, interventional 
endoscopy with EUS and ERCP assistance as well as surgical expertise in managing 
necrotizing pancreatitis. Patients should be enrolled in prospective audits for quality control 
issues and into clinical trials whenever possible. (GRADE 2C, weak agreement) 
14. Early fluid resuscitation within the first 24 hours of admission for acute pancreatitis is 
associated with decreased rates of persistent SIRS and organ failure. (GRADE 1C, strong 
agreement) 
15. Abdominal compartment syndrome (ACS) is defined as a sustained intra-abdominal 
pressure > 20 mmHg that is associated with new onset organ failure. (GRADE 2B, strong 
agreement) 
16. Medical treatment of ACS should target 1) hollow-viscera volume, 2) intra/extra vascular 
fluid and 3) abdominal wall expansion. Invasive treatment should only be used after 
multidisciplinary discussion in patients with a sustained intra-abdominal pressure >25mmHg 
with new onset organ failure refractory to medical therapy and nasogastric/ rectal 
decompression. Invasive treatment options include percutaneous catheter drainage of ascites, 
midline laparostomy, bilateral subcostal laparostomy, or subcutaneous linea alba fasciotomy. In 


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case of surgical decompression, the retroperitoneal cavity and the omental bursa should be left 
intact to reduce the risk of infecting peripancreatic and pancreatic necrosis. (GRADE 2C, 
strong agreement) 
F. Preventing Infectious Complications 
17. Intravenous antibiotic prophylaxis is not recommended for the prevention of infectious 
complications in acute pancreatitis. (GRADE 1B, strong agreement) 
18. Selective gut decontamination has shown some benefits in preventing infectious 
complications in acute pancreatitis, but further studies are needed. (GRADE 2B, weak 
agreement) 
19. Probiotic prophylaxis is not recommended for the prevention of infectious complications in 
acute pancreatitis. (GRADE 1B, strong agreement) 
G. Nutritional Support 
20. Oral feeding in predicted mild pancreatitis can be restarted once abdominal pain is 
decreasing and inflammatory markers are improving. (GRADE 2B, strong agreement) 
21. Enteral tube feeding should be the primary therapy in patients with predicted severe acute 
pancreatitis who require nutritional support. (GRADE 1B, strong agreement) 
22. Either elemental or polymeric enteral nutrition formulations can be used in acute 
pancreatitis. (GRADE 2B, strong agreement) 
23. Enteral nutrition in acute pancreatitis can be administered via either the nasojejunal or 
nasogastric route. (GRADE 2A, strong agreement) 
24. Parenteral nutrition can be administered in acute pancreatitis as second-line therapy if 
nasojejunal tube feeding is not tolerated and nutritional support is required. (GRADE 2C, 
strong agreement) 
H. Biliary Tract Management 
25. ERCP is not indicated in predicted mild biliary pancreatitis without cholangitis. (GRADE 
1A, strong agreement) ERCP is probably not indicated in predicted severe biliary pancreatitis 
without cholangitis. (GRADE 1B, strong agreement) ERCP is probably indicated in biliary 
pancreatitis with common bile duct obstruction. (GRADE 1C, strong agreement) ERCP is 
indicated in patients with biliary pancreatitis and cholangitis. (GRADE 1B, strong agreement) 
26. Urgent ERCP (<24 hrs) is required in patients with acute cholangitis. Currently, there is no 
evidence regarding the optimal timing of ERCP in patients with biliary pancreatitis without 
cholangitis.(GRADE 2C, strong agreement) 
27. MRCP and EUS may prevent a proportion of ERCPs that would otherwise be performed 
for suspected common bile duct stones in patients with biliary pancreatitis who do not have 
cholangitis, without influencing the clinical course. EUS is superior to MRCP in excluding the 
presence of small (<5mm) gallstones. MRCP is less invasive, less operator-dependent and 
probably more widely available than EUS. Therefore, in clinical practice there is no clear 
superiority for either MRCP or EUS. (GRADE 2C, strong agreement) 


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I. Indications for Intervention in Necrotizing Pancreatitis 
28. Common indications for intervention (either radiological, endoscopical or surgical) in 
necrotizing pancreatitis are: 1) Clinical suspicion of, or documented infected necrotizing 
pancreatitis with clinical deterioration, preferably when the necrosis has become walled-off, 2) 
In the absence of documented infected necrotizing pancreatitis, ongoing organ failure for 
several weeks after the onset of acute pancreatitis, preferably when the necrosis has become 
walled-off. (GRADE 1C, strong agreement) 
29. Routine percutaneous fine needle aspiration of peripancreatic collections to detect bacteria 
is not indicated, because clinical signs (i.e. persistent fever, increasing inflammatory markers) 
and imaging signs (i.e. gas in peripancreatic collections) are accurate predictors of infected 
necrosis in the majority of patients. Although the diagnosis of infection can be confirmed by 
fine needle aspiration (FNA), there is a risk of false-negative results. (GRADE 1C, strong 
agreement) 
30. Indications for intervention (either radiological, endoscopical or surgical) in sterile 
necrotizing pancreatitis are: 1) Ongoing gastric outlet, intestinal, or biliary obstruction due to 
mass effect of walled-off necrosis (i.e. arbitrarily >4-8 weeks after onset of acute pancreatitis), 
2) Persistent symptoms (e.g. pain, ‘persistent unwellness’) in patients with walled-off necrosis 
without signs of infection (i.e. arbitrarily >8 weeks after onset of acute pancreatitis), 3) 
Disconnected duct syndrome (i.e. full transection of the pancreatic duct in the presence of 
pancreatic necrosis) with persisting symptomatic (e.g. pain, obstruction) collection(s) with 
necrosis without signs of infections (i.e. arbitrarily >8 weeks after onset of acute pancreatitis). 
(GRADE 2C, strong agreement) 
J. Timing of Intervention in Necrotizing Pancreatitis 
31. For patients with proven or suspected infected necrotizing pancreatitis, invasive 
intervention (i.e. percutaneous catheter drainage, endoscopic transluminal 
drainage/necrosectomy, minimally invasive or open necrosectomy) should be delayed where 
possible until at least 4 weeks after initial presentation to allow the collection to become 
‘walled-off’. (GRADE 1C, strong agreement) 
32. The best available evidence suggests that surgical necrosectomy should ideally be delayed 
until collections have become walled-off, typically 4 weeks after the onset of pancreatitis, in all 
patients with complications of necrosis. No subgroups have been identified that might benefit 
from earlier or delayed intervention. (GRADE 1C, strong agreement) 
I. Intervention Strategies in Necrotizing Pancreatitis 
33. The optimal interventional strategy for patients with suspected or confirmed infected 
necrotizing pancreatitis is initial image-guided percutaneous (retroperitoneal) catheter drainage 
or endoscopic transluminal drainage, followed, if necessary, by endoscopic or surgical 
necrosectomy. (GRADE 1A, strong agreement) 
34. Percutaneous catheter or endoscopic transmural drainage should be the first step in the 
treatment of patients with suspected or confirmed (walled-off) infected necrotizing pancreatitis. 
(GRADE 1A, strong agreement) 


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35. There are insufficient data to define subgroups of patients with suspected or confirmed 
infected necrotizing pancreatitis who would benefit from a different treatment strategy. 
(GRADE 2C, strong agreement) 
J. Timing of Cholecystectomy (or Endoscopic Sphincterotomy) 
36. Cholecystectomy during index admission for mild biliary pancreatitis appears safe and is 
recommended. Interval cholecystectomy after mild biliary pancreatitis is associated with a 
substantial risk of readmission for recurrent biliary events, especially recurrent biliary 
pancreatitis. (GRADE 1C, strong agreement) 
37. Cholecystectomy should be delayed in patients with peripancreatic collections until the 
collections either resolve or if they persist beyond 6 weeks, at which time cholecystectomy can 
be performed safely. (GRADE 2C, strong agreement) 
38. In patients with biliary pancreatitis who have undergone sphincterotomy and are fit for 
surgery, cholecystectomy is advised, because ERCP and sphincterotomy prevent recurrence of 
biliary pancreatitis but not gallstone related gallbladder disease, i.e. biliary colic and 
cholecystitis. (GRADE 2B, strong agreement) 


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Appendix 8 
Pain Numeric Rating Scale (PNRS) 
 


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Appendix 9 
The Critical-Care Pain Observation Tool (CPOT) 
Adapted from Gélinas 2006 
 


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Appendix 10 APACHE II Score 
Physiological Variable 
+4 
+3 
+2 
+1 
0 
+1 
+2 
+3 
+4 
1. Temperature (°C) 
≥41 
39.0-40.9 
 
38.5-38.9 
36-38.4 
34-35.9 
32-33.9 
30-31.9 
≤29.9 
2. Mean Arterial Pressure 
(mmHg) 
≥160 
130-159 
110-129 
 
70-109 
 
50-69 
 
≤49 
3. Heart Rate 
≥180 
140-179 
110-139 
 
70-109 
 
55-69 
40-54 
≤39 
4. Respiratory Rate 
≥50 
35-49 
 
25-34 
12-24 
10-11 
6-9 
 
≤5 
5. Oxygenation 
 
 
 
 
 
 
 
 
 
− FiO2 ≥0.5, record A-aDO2 
≥500 
350-499 
200-349 
 
<200 
 
 
 
 
− FiO2 <0.5, record PaO2 
 
 
 
 
>70 
61-70 
 
55-60 
<55 
6. pH 
≥7.7 
7.6-7.69 
 
7.5-7.59 
7.33-7.49 
 
7.25-7.32 
7.15-7.24 
<7.15 
- Serum HCO3 (mmol/L) 
≥52 
41-51.9 
 
32-40.9 
22-31.9 
 
18-21.9 
15-17.9 
<15 
7. Serum sodium (mmol/L) 
≥180 
160-179 
155-159 
150-154 
130-149 
 
120-129 
111-119 
≤110 
8. Serum potassium (mmol/L) 
≥7.0 
6.0-6.9 
 
5.5-5.9 
3.5-5.4 
3.0-3.4 
2.5-2.9 
 
<2.5 
9. Serum creatinine (mg/dL) 
Double score for AKI 
≥3.5 
2.0-3.4 
1.5-1.9 
 
0.6-1.4 
 
<0.6 
 
 
10. Hematocrit (%) 
≥60 
 
50-59.9 
46-49.9 
30-45.9 
 
20-29.9 
 
<20 
11. WBC count (1000/mm3) 
≥40 
 
20-39.9 
15-19.9 
3.0-14.9 
 
1.0-2.9 
 
<1.0 
12. Glasgow coma scale 
15-(GCS score) 
Total Acute Physiology Score 
Sum of the 12 Physiological Variables 
Points for Age 
Points for Chronic Health Condition 
If the patient has a history of severe organ system insufficiency or is immunocompromised, assign the following 
points: 
For elective post-operative patients: 2 points; 
For emergent post-operative patients: 5 points; 
For non-operative patients: 5 points. 
Age 
Points 
≤ 44 
0 
45-54 
2 
55-64 
3 
65-74 
5 
≥75 
6 
APACHE II score= Total Acute Physiology Score + Points for Age + Points for Chronic Health 
Adapted from Knaus 1985 


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Appendix 11 Schedule of Events 
 
Screen 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Days 6,7 
Days 8,9 
Day10h 
Days 12-28a Day 30b 
Day 90c 
Informed Consent 
X 
 
Demographics & Medical History 
X 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination (limited) 
X 
 
X 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and Weight 
X 
 
Serum Pregnancy Test for WOCBP 
X 
Blood sample for amylase or lipased 
X 
Determine Presence of SIRSd 
X 
Blood Sample for Serum Chemistries 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Sample for CBC, Diff & Plateletse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood and Urine Sample for Biomarkers  
 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Sample for PK Analysisf 
 
X 
X 
 
X 
X 
 
X 
Arterial Blood Gasg 
 
X 
 
X 
 
X 
SpO2 by Pulse Oximetry and FiO2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Calculate Glasgow Coma Scale Score 
 
X 
X 
X 
X 
X 
X 
X 
X 
CECT of the Pancreas 
X 
 
X (Day 5 to Day 7) 
 
Assess Pain 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomize patienti 
 
X 
 
AE/SAE Evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CM4620-IE Administration 
 
X 
X 
X 
X 
 
 
                                                 
a 
Safety and tolerability assessments after Day 10 will be done every 48 hours until Day 30 or until discharge, whichever occurs first 
b Day 30 visit (± 2 days): for patients who have been discharged prior to Day 30, the visit will consist of a telephone call to the patient, the LAR, or the primary MD, or chart a review for an SAE evaluation and 
to determine if patient has had a readmission to the hospital.  
c 
Day 90 (± 7 days) visit will consist of a telephone call to the patient, the LAR, or the primary MD, or chart a review for mortality. 
d Blood samples for amylase or lipase and CBC, Diff and platelets at screening will be analyzed at local lab. SIRS will determined using local labs at screening 
e 
Vital signs and CBC, differential and platelets drawn every 12 hours on Days 1-5. 
f 
A PK sample will be obtained 30 minutes (± 15 min) after and 8 hours (± 30 min) after completion of CM4620-IE administration on Day 1 and Day 4. A PK sample will be obtained 30 minutes prior to 
administration of CM4620-IE on Day 2. On Day 5, and on Day 10, or discharge if earlier, a PK sample will be obtained. 
g If an ABG is performed as standard of care, the pH, PaO2, PaCO2, SaO2 and FiO2 will be recorded. 
h Day 10 procedures will be performed if the patient is discharged prior to Day 10 
i 
Randomization will only occur after Day 1 procedures to record concomitant medications, vital signs, draw blood and urine samples, obtain SpO2 and FiO2 measurements, calculate Glasgow Coma Scale score 
and assess pain scores completed 

SAP_001.pdf: 
Protocol Number: CM4620-201 
CTC Project Code: 188_18_2018 
 
 
Template ID: BM004Temp01_01_SP 
 
 
 
 
 
 
CONFIDENTIAL 
Statistical Analysis Plan (SAP) 
___________________________________________________________ 
 
Sponsor: 
CalciMedica through EMAS 
Study code: 
CM4620-201 
Study title: 
An Open-Label, Dose-Response Study of 
CM4620 Injectable Emulsion in Patients with 
Acute Pancreatitis and Accompanying 
Systemic Inflammatory Response Syndrome 
(SIRS) 
Date: 
Draft 1 – 03OCT2018 
Final_draft – 01MAR2019  
FINAL – 03MAR2019 
 
 
 


 Protocol Number: CM4620-201 
CTC Project Code: 188_18_2018 
 
Statistical Analysis Plan version 1.0 
 
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TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS ...................................................................................................................... 5 
2 
INTRODUCTION ........................................................................................................................................ 6 
3 
CLINICAL STUDY DETAILS .................................................................................................................... 6 
3.1 
Clinical Study Objectives.......................................................................................................... 6 
3.1.1 
Primary objective ............................................................................................................. 6 
3.1.2 
Primary endpoint ............................................................................................................. 6 
3.1.3 
Secondary objectives ....................................................................................................... 6 
3.1.4 
Secondary endpoints ....................................................................................................... 6 
3.2 
Clinical Study Design ................................................................................................................ 7 
3.3 
Number of Subjects ................................................................................................................. 8 
3.4 
Methods of Assigning Subject to IMP ..................................................................................... 8 
3.5 
Blinding .................................................................................................................................... 8 
4 
STATISTICAL AND ANALYTICAL PLANS........................................................................................... 8 
4.1 
General .................................................................................................................................... 8 
4.2 
Sample Size Justification .......................................................................................................... 9 
4.3 
Definition of Analysis Sets ....................................................................................................... 9 
4.3.1 
Full Analysis Set ............................................................................................................... 9 
4.3.2 
Per Protocol Set ............................................................................................................... 9 
4.3.3 
Use of analysis set .............................................................Error! Bookmark not defined. 
4.4 
Definition of Baseline .............................................................................................................. 9 
4.5 
Summary Statistics .................................................................................................................. 9 
4.6 
Significance Level..................................................................................................................... 9 
4.7 
Multiple Comparisons/Multiplicity ......................................................................................... 9 
4.8 
Handling of Drop-outs, Missing Data and Outliers .................................................................. 9 
4.9 
Adjustment for Covariates ...................................................................................................... 9 
4.10 
Multicenter Studies ................................................................................................................. 9 
4.11 
Examination of Subgroups....................................................................................................... 9 
4.12 
Blind Review ............................................................................................................................ 9 
5 
SUBJECTS ................................................................................................................................................. 10 
5.1 
Subject Disposition ................................................................................................................ 10 
5.2 
Baseline Characteristics and Demographics .......................................................................... 10 
6 
TREATMENT INFORMATION AND EXTENT OF EXPOSURE .................................................... 10 
6.1 
Active Treatment ................................................................................................................... 10 
6.2 
Prior and Concomitant Medications ..................................................................................... 10 
7 
STATISTICAL METHODOLOGY ......................................................................................................... 10 


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7.1 
Primary endpoint(s) ............................................................................................................... 10 
7.1.1 
Definition ....................................................................................................................... 10 
7.1.2 
Analysis .......................................................................................................................... 10 
7.1.3 
Presentation .................................................................................................................. 10 
7.2 
Secondary Endpoints - CTSI ................................................................................................... 10 
7.2.1 
Definition ....................................................................................................................... 10 
7.2.2 
Analysis .......................................................................................................................... 11 
7.2.3 
Presentation .................................................................................................................. 11 
7.3 
Secondary Endpoints - PASS score ........................................................................................ 11 
7.3.1 
Definition ....................................................................................................................... 11 
7.3.2 
Analysis .......................................................................................................................... 13 
7.3.3 
Presentation .................................................................................................................. 13 
7.4 
Secondary Endpoints – Solid food ......................................................................................... 13 
7.4.1 
Definition ....................................................................................................................... 13 
7.4.2 
Analysis .......................................................................................................................... 13 
7.4.3 
Presentation .................................................................................................................. 13 
7.5 
Secondary Endpoints - Biomarker ......................................................................................... 13 
7.5.1 
Definition ....................................................................................................................... 13 
7.5.2 
Analysis .......................................................................................................................... 14 
7.5.3 
Presentation .................................................................................................................. 14 
7.6 
Secondary Endpoints - SIRS ................................................................................................... 14 
7.6.1 
Definition ....................................................................................................................... 14 
7.6.2 
Analysis .......................................................................................................................... 14 
7.6.3 
Presentation .................................................................................................................. 14 
7.7 
Secondary Endpoints – Organ failure .................................................................................... 14 
7.7.1 
Definition ....................................................................................................................... 14 
7.7.2 
Analysis .......................................................................................................................... 15 
7.7.3 
Presentation .................................................................................................................. 15 
7.8 
Secondary Endpoints – SOFA score ....................................................................................... 15 
7.8.1 
Definition ....................................................................................................................... 15 
7.8.2 
Analysis .......................................................................................................................... 16 
7.8.3 
Presentation .................................................................................................................. 16 
7.9 
Secondary Endpoints - Revised Atlantic Classification of Acute Pancreatitis ....................... 16 
7.9.1 
Definition ....................................................................................................................... 16 
7.9.2 
Analysis .......................................................................................................................... 17 
7.9.3 
Presentation .................................................................................................................. 17 
7.10 
Secondary Endpoints - Determinant Based Classification of Acute Pancreatitis .................. 17 


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7.10.1 
Definition ....................................................................................................................... 17 
7.10.2 
Analysis .......................................................................................................................... 17 
7.10.3 
Presentation .................................................................................................................. 17 
7.11 
Secondary Endpoints - Pain Numeric Rating Scale (PNRS) .................................................... 17 
7.11.1 
Definition ....................................................................................................................... 17 
7.11.2 
Analysis .......................................................................................................................... 18 
7.11.3 
Presentation .................................................................................................................. 18 
7.12 
Secondary Endpoints - Critical-Care Pain Observation Tool (CPOT) ..................................... 18 
7.12.1 
Definition ....................................................................................................................... 18 
7.12.2 
Analysis .......................................................................................................................... 19 
7.12.3 
Presentation .................................................................................................................. 19 
7.13 
Secondary Endpoints - Overall Survival ................................................................................. 20 
7.13.1 
Definition ....................................................................................................................... 20 
7.13.2 
Analysis .......................................................................................................................... 20 
7.13.3 
Presentation .................................................................................................................. 20 
7.14 
Secondary Endpoints – Hospitalization days ......................................................................... 20 
7.14.1 
Definition ....................................................................................................................... 20 
7.14.2 
Analysis .......................................................................................................................... 20 
7.14.3 
Presentation .................................................................................................................. 20 
7.15 
Discontinuation ..................................................................................................................... 20 
7.16 
Interim Analysis ..................................................................................................................... 20 
8 
CHANGES FROM THE CSP ................................................................................................................... 20 
9 
STATISTICAL DELIVERABLES ........................................................................................................... 20 
10 
SOFTWARE ......................................................................................................................................... 21 
11 
APPROVAL .......................................................................................................................................... 22 
 
 
 


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1 
LIST OF ABBREVIATIONS 
AE – Adverse Event 
ALB - Albumin 
ATC – Anatomical-Therapeutic-Chemical 
CF – Clean File  
CRF – Case Report Form 
CSP – Clinical study protocol 
FAS – Full Analysis Set 
HCT - Hematocrit 
MedDRA – Medical Dictionary for Regulatory Affairs 
PPS – Per Protocol Set 
SAE – Serious Adverse Event 
SAP – Statistical Analysis Plan 
SAS – Statistical Analysis System 
SD – Standard Deviation 
 
 


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2 
INTRODUCTION 
This Statistical Analysis Plan (SAP) gives details regarding the statistical analyses and data 
presentation outlined in the final Clinical study protocol (CSP) for the study CM4620-201. Any 
changes from the final CSP are given in Section 8. This needs to be approved and signed prior to 
database lock. 
 
3 
CLINICAL STUDY DETAILS 
3.1 Clinical Study Objectives 
3.1.1 Primary objective 
To assess the safety and tolerability of CM4620-IE in patients with acute pancreatitis and 
accompanying SIRS 
3.1.2 Primary endpoint 
The primary endpoints of the study are related to safety, these include Adverse Events (AEs), 
Vital Signs (VS) and safety laboratory measures 
3.1.3 Secondary objectives 
To assess the efficacy of CM4620-IE in patients with acute pancreatitis and accompanying SIRS 
To determine the pharmacokinetic profile of CM4620-IE in patients with acute pancreatitis and 
accompanying SIRS 
3.1.4 Secondary endpoints 
The secondary efficacy endpoints are: 
 
CTSI Score categorized into Mild, Moderate and Severe 
 
Balthazar score  
 
Pancreatic Parenchymal Necrosis 
o < 30% 
o 30-50% 
o > 50% 
 
PASS score 
 
Tolerating Solid Food 
o Time to tolerating solid food 
o Arithmetic mean of time to tolerate 50% solid food  
 
Biomarker measurements including, but not limited to:  
o ANC/ALC (Absolute neutrophils count / Absolute Lymphocytes count) 
o C-Reactive Protein (CRP) 
o D-Dimer  


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o Procalcitonin  
o Il-6 
o Il-8  
 
SIRS  
o Time to resolution of SIRS 
o The number of days alive and free from SIRS 
o Total SIRS score 
 
Any Organ Failure (LISTINGS) 
 
Respiratory Failure (LISTINGS) 
 
Renal Failure (LISTINGS) 
 
Cardiovascular Failure (LISTINGS) 
 
Sequential Organ Failure Assessment (SOFA):  
o Respiration Score 
o Coagulation Score 
o Liver Score 
o Cardiovascular Score  
o Central Nervous System Score 
o Renal Score 
o SOFA total Score 
 
Modified Sequential Organ Failure Assessment (MSOFA):  
o Modified total SOFA Score 
 
Severity as defined by Revised Atlantic Classification of Acute Pancreatitis 
 
Severity as defined by Determinant Based Classification of Acute Pancreatitis 
 
APACHE II score 
 
Pain Numeric Rating Scale (PNRS) score 
 
Critical-Care Pain Observation Tool (CPOT) score 
 
Overall Survival (Listings) 
 
Number of hospitalized days  
o Total Days 
o Days in Intensive Care 
3.2 Clinical Study Design 
This open-label, dose-response study will evaluate the safety and efficacy of CM4620-IE in 
patients with acute pancreatitis and accompanying SIRS. The study will consist of two phases. 
The first phase will consist of 2 cohorts that will be enrolled concurrently. Cohort 1 will consist 
of 4 female patients who will be randomized 3:1 to receive CM4620-IE plus supportive care 
versus supportive care alone. Cohort 2 will consist of 4 male patients who will be randomized 


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3:1 to receive CM4620-IE plus supportive care versus supportive care alone. Planned doses for 
patients in both cohorts who are randomized to receive CM4620-IE are 1.0 mg/kg on Day 1 and 
1.4 mg/kg on Days 2-4. The first infusion of CM4620-IE must be started within 6 (up to 8) hours 
of the patient or LAR providing informed consent and should be administered IV over 4 hours. 
Subsequent infusions will be started every 24 hours (± 1 hour) from the start of the first 
infusion. 
The second phase will consist of 2 cohorts. Cohort 3 will consist of 8 female patients who will be 
randomized 3:1 to receive CM4620-IE plus supportive care versus supportive care alone. Cohort 
4 will consist of 8 male patients who will be randomized 3:1 to receive CM4620-IE plus 
supportive care versus supportive care alone. Planned doses for patients in both cohorts who 
are randomized to receive CM4620-IE are 2.08 mg/kg of CM4620-IE on Days 1 and 2, and 1.6 
mg/kg on Days 3 and 4. The first infusion of CM4620-IE must be started within 6 (up to 8) hours 
of the patient or LAR providing informed consent and will be administered intravenously IV over 
4 hours. Subsequent infusions will be started every 24 hours (± 1 hour) from the start of the first 
infusion. 
The decision to start Cohort 3 will be made after CalciMedica reviews the available efficacy, 
safety and tolerability data from Cohort 1 and discusses with the Principal Investigators. The 
decision to start Cohort 4 in the second phase of the study will be made after CalciMedica 
reviews the available efficacy, safety and tolerability data from Cohort 2 and discusses with the 
Principal Investigators. 
For all 4 cohorts, a study physician or appropriately trained delegate will perform all 
assessments daily through Day 10, or until discharge if occurring earlier. After Day 10, and 
starting on Day 12, serious adverse events (SAEs) will be captured every 48 hours until Day 30 (± 
2 days), or until discharge if occurring earlier. Patients discharged prior to Day 30 will be 
contacted on Day 30 (± 2 days) to capture SAEs and any re-admissions to the hospital. Patients 
will also be contacted on Day 90 (± 7 days) to assess mortality. 
3.3 Number of Subjects 
24 randomized subjects 
3.4 Methods of Assigning Subject to IMP 
Patients will be randomized 3:1 to receive CM4620-IE in addition to supportive care consistent 
with the 2013 IAP/APA evidence-based guidelines for the management of acute pancreatitis 
versus supportive care alone. Randomization will be stratified by sex. CalciMedica or its 
designee will prepare the randomization schedule prior to the start of the study 
3.5 Blinding 
Not applicable 
4 
STATISTICAL AND ANALYTICAL PLANS 
4.1 General 
All endpoints below will be presented by: 
1) All cohorts 
If there will be some exploratory hypothesis testing performed a 5% significance level will be 
used. 
 


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4.2 Sample Size Justification 
This open-label study will enroll 24 patients. The sample size was selected based on practical 
considerations to initially evaluate the safety, efficacy and pharmacokinetic profile of CM4620-IE 
in patients with acute pancreatitis and accompanying SIRS. This study is not powered for 
analysis of study data with inferential statistics 
4.3 Definition of Analysis Sets 
4.3.1 Full Analysis Set  
The Full Analysis Set (FAS) consists of all randomized patients who receive any amount of 
CM4620-IE or supportive care.  Patients will be analyzed according to treatment they actually 
received. 
4.3.2 Per Protocol Set 
No Per Protocol Set will be used. 
4.4 Definition of Baseline 
Baseline measurement is defined as the latest measurement prior to first dose of IMP including 
Apache II score. 
4.5 Summary Statistics 
In general, all data collected will be presented with summary statistics and given in patient data 
listings. Summary statistics will include at least number of patients, mean, standard deviation, 
median, minimum and maximum for continuous data and frequency and percentage for 
categorical data. Table with summary statistics will be divided by treatment group and dose 
group, and visit where applicable. Patient data listings will be sorted by treatment, subject and 
timing of assessments. 
For confidence intervals for proportions will the Clopper-Pearson exact formula be used. 
4.6 Significance Level 
If applicable will 5% significance level be used. 
4.7 Multiple Comparisons/Multiplicity 
No adjustment for multiple comparison/multiplicity will be performed, all significant statistical 
findings, must be reviewed for medical relevance.  
4.8 Handling of Drop-outs, Missing Data and Outliers  
Outliers will be included in summary tables and listings, and will not be handled separately in 
any analyses. No imputation of missing data will be performed (however, will data entered in 
unscheduled visit be placed to the nearest applicable visit with missing values). 
4.9 Adjustment for Covariates 
Not applicable  
4.10 Multicenter Studies 
No adjustment for sites will be performed. 
4.11 Examination of Subgroups 
Gender and HCT/ALB will be used as subgroups for all secondary endpoints. 
4.12 Blind Review 
Not applicable. 


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5 
SUBJECTS 
5.1 Subject Disposition 
The number of subjects that entered the study, withdrawn subjects, completed subjects and the 
number of subjects at each visit will be summarized by treatment. 
5.2 Baseline Characteristics and Demographics 
All baseline and demographic data will be presented using summary statistics. 
6 
TREATMENT INFORMATION AND EXTENT OF EXPOSURE 
6.1 Active Treatment 
The number of subjects on each IP will be tabulated with start time, stop time and duration of 
application will be tabulated using listings and summary statistics.  
6.2 Prior and Concomitant Medications 
Prior and concomitant medication data will be listed and tabulated by ATC code. Prior and 
concomitant medications will be coded according to the World Health Organization (WHO Drug 
Dictionary) classification system. 
7 
STATISTICAL METHODOLOGY 
All parameters will be presented by treatment and visit using summary statistics. Additional 
statistical analyses are specified below. 
7.1 Primary endpoint(s) 
7.1.1 Definition 
The adverse event will be coded using MeDRA dictionary.  
Absolute and percent change from baseline will be calculated for both the vital signs and 
laboratory parameters. 
7.1.2 Analysis 
The adverse events will be analyzed using frequencies and percent divided by SOC, and PT code 
using the TESS approach. 
The vital signs will be presented using summary statistics by visit. 
Safety laboratory parameters will be presented using shift tables. 
7.1.3 Presentation 
The adverse events will be present using frequency tables. 
 
7.2 Secondary Endpoints – CTSI and mCTSI 
7.2.1 Definition 
Balthazar score is classified according to the table below 
Grade
CT Finding Balthazar 
Points
A
Normal Pancreas
0
B
Enlargement of Pancreas
1
C
Inflammatory changes in pancreas and peripancreatic fat
2


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D
Ill-defined single peripancreatic fluid collection
3
E
Two or more poorly defined peripancreatic fluid collections
4
 
Pancreatic Parenchymal Necrosis is classified as: 
Pancreatic Necrosis Points
None
0
<30%
2
30-50%
4
>50%
6
 
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 
 
Change for the category of the severity of acute pancreatitis by CTSI score  will be calculated 
from baseline to day 5 and later dates as necessary. 
7.2.2 Analysis 
No statistical test will be performed on these variables. 
7.2.3 Presentation 
Each individual scale will be presented both by using summary statistics in tables and frequency 
tables. 
The total scores will be presented using summary statistics. 
 
7.3 Secondary Endpoints - PASS score 
7.3.1 Definition 
The definition of the PASS score is in accordance with the description below: 
Calculated every 12 hours from 1st vital signs taken in the Emergency Department 
 
Organ Failure Score: # Organs x 100 for each system 
 
Organ Failure Definition: Modified Marshall Scoring System (adapted from Banks 
et al4) 


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 
Mechanical ventilation counts as respiratory organ failure 
 
New onset dialysis included as renal failure 
 
SIRS (Systemic Inflammatory Response Syndrome): # SIRS Criteria satisfied x 25 for each 
criteria. (See below) 
 
Heart Rate > 90 beats per minute 
 
Temperature > 38 Celsius or < 36 Celsius 
 
White blood cell count < 4000 or > 12000 
 
Respiration > 20/minute 
 
Take the most extreme value within each 12 hour window 
Take the WBC from the most recent prior CBC if none available in a given 12 hour 
window 
 
Abdominal Pain Score: Abdominal pain (0-10) x 5 
 
Highest numerical value in each 12 hour window 
 
Morphine Equivalent Dose Score: Morphine Equivalent Dose x 5 
 
For consistency will be using IV MED (typical MED is for oral) 
 
Common conversions:  (easiest to convert to IV) 
 
Morphine IV to PO is 1 to 3 (ie morphine 10 mg IV = 30 mg PO)  
 
Dilaudid IV to PO is 1 to 4 (ie dilaudid 1.5 mg IV = 7.5 mg PO) 
 
Dilaudid IV to Morphine IV is 1:7 
 
Note: 1 po MED = 30 mg oral morphine 
 
(refer to tables for more specific conversion) 
 
Parenteral
Oral
Morphine
10
30
Buprenorphine
0.3
0.4 (sl)
Codeine
100
200
Fentanyl
0.1
NA
Hydrocodone
NA
30
Hydromorphone
1.5
7.5
Meperidine
100
300
Oxycodone
10
20
Oxymorphone
1
10
Tramadol
100
120
Equianalgesic dose conversions. For calculation of Pancreatitis Activity Score: 


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 1 MED (morphine equivalent dose) = 1 mg parenteral morphine = 3 mg oral morphine. 
 
Tolerating Solid Diet Score: (yes=0, no=1) x 40 
 
Retrospective analysis: based on change in diet order  
 
Prospective analysis: tolerating at least 50% of solid meal without increase abdominal 
pain or vomiting 
 
 
Then calculate the total score including absolute and percent change from baseline 
7.3.2 Analysis 
No analyses will be performed 
7.3.3 Presentation 
The PASS score will be presented using summary statistics and presented in tables and graphs. 
The graphs will be the mean value at each visit including the 2-standard error of the mean. 
 
7.4 Secondary Endpoints – Solid food 
7.4.1 Definition 
The definition of tolerating solid food is that at least 50% is tolerated. Then will the time to first 
occurrence of tolerating solid food be calculated as date of tolerating solid food – date of 
randomization +1. 
At each visit will tolerating solid food be coded into yes or no. 
7.4.2 Analysis 
No analyses will be performed 
7.4.3 Presentation 
The variable tolerating food as yes/no will be presented using frequency tables. 
The variable tolerating food as percentage will be presented using summary statistics. 
 
7.5 Secondary Endpoints - Biomarker 
7.5.1 Definition 
The following biomarkers will be used in the analyses.  
ANC/ALC (Absolute neutrophils count / Absolute Lymphocytes count) 
C-Reactive Protein (CRP) 
D-Dimer  
Procalcitonin  
Il-6 
Il-8  
Absolute and percent change will be calculated for each biomarker. 


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7.5.2 Analysis 
No statistical tests will be performed. 
7.5.3 Presentation 
All biomarkers will be presented using summary statistics and graphs showing both the mean, 
absolute and percent change over time. 
7.6 Secondary Endpoints - SIRS 
7.6.1 Definition 
SIRS consist of 4 components; temperature of < 36°C or > 38°C, heart rate > 90 beats per 
minute, respiratory rate >20 breaths per minute or PaCO2 < 32 mmHg and white blood cells 
(WBC) > 12,000 mm3, <4000mm3 or > 10% immature band forms.  SIRS is present if two or more 
of the 4 components are identified.  If any of the 4 components are missing, that component will 
not contribute to the SIRS evaluation. 
The total SIRS score is the sum of all SIRS components at each time point  
Time to resolution of SIRS will be defined as time from randomization to first sign of resolution 
of SIRS. 
The number of days alive and free from SIRS 
7.6.2 Analysis 
No statistical tests will be performed. 
7.6.3 Presentation 
The total score of SIRS will be presented using summary statistics.  
 
7.7 Secondary Endpoints – Organ failure 
7.7.1 Definition 
Respiratory Failure  
The presence of respiratory failure will be assessed on Days 1-10. 
Respiratory failure is defined as PaO2/FiO2 ≤300, either determined by ABG or calculated from 
the SpO2/FiO2 or the use of non-invasive or invasive mechanical ventilation (respiratory 
support). 
Renal Failure  
• 
An increase in serum creatinine ≥300% if the baseline creatinine is known from prior to the 
hospitalization for acute pancreatitis, or 
• 
A serum creatinine ≥1.9 mg/dL, or 
• 
The initiation of renal replacement therapy 
For patients with pre-existing chronic kidney disease, organ failure will be defined as: 
• 
An increase in serum creatinine ≥300% if the baseline creatinine is known from prior 
to the hospitalization for acute pancreatitis, or 
• 
An increase of serum creatinine to a level >4.0 mg/dl, or 


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• 
The initiation of renal replacement therapy 
Cardiovascular Failure  
The presence of cardiovascular failure will be assessed on Days 1-10.  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 
 
Any Organ Failure  
If the patient meets the conditions for at least one type of organ failure (respiratory failure, 
renal failure or cardiovascular failure), they have a diagnosis of Organ Failure.  If they meet the 
conditions for more than one organ failure they also have a diagnosis of multiple organ failure.  
Patients free from all types or organ failure or without data to support diagnosis of organ 
failure, do not have organ failure 
Transient organ failure 
Patients with transient organ failure are identified by organ failure lasting less than 48 hours.  
Persistent organ failure is documented for greater or equal to 48 hours. New persistent Organ 
Failure is only applicable for patients without Organ Failure at baseline. 
7.7.2 Analysis 
No statistical tests will be performed. 
7.7.3 Presentation 
All organ failure variables will only be presented in listings together with the definition variables. 
 
7.8 Secondary Endpoints – SOFA score 
7.8.1 Definition 
The total SOFA score will be calculated using all including parts: 
Respiration Score, Coagulation Score, Liver Score, Cardiovascular Score, Central Nervous System 
Score, Renal Score in accordance to: 
 


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The Modified Sequential Organ Failure Assessment (MSOFA) total score will be calculated 
excluding the Central Nervous System Score. 
Absolute and percent changes for each including item and total score will be calculated. 
7.8.2 Analysis 
No statistical tests will be performed. 
7.8.3 Presentation 
All including item and total scores will be presented using summary statistics. 
 
7.9 Secondary Endpoints - Revised Atlantic Classification of Acute Pancreatitis 
7.9.1 Definition 
Revised Atlanta Classification of Acute Pancreatitis, is determined by transient or persistent 
organ failure (Section 7.7), and local or systemic complications (systemic complications is 
defined as exacerbation of pre-existing comorbidity). 
 
Grades of Severity 
Mild 
No organ failure 
No local or systemic complications
Moderately Severe 
Organ failure that resolves within 48 hours and/or 
Local or systemic complications without organ failure
Severe 
Persistent Organ Failure
 


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7.9.2 Analysis 
No statistical tests will be performed. 
7.9.3 Presentation 
The Revised Atlantic Classification of Acute Pancreatitis will be presented using frequency 
tables. 
 
7.10 Secondary Endpoints - Determinant Based Classification of Acute Pancreatitis 
7.10.1 Definition 
Severity as defined by Determinant Based Classification of Acute Pancreatitis will be provided by 
CalciMedica in excel format in accordance to by subject: 
 
Mild AP
Moderate AP
Severe AP
Critical AP
(Peri)pancreatic 
necrosis
No 
Sterile 
Infected 
Infected 
And
And/Or
Or
And
Organ Failure 
No 
Transient 
Persistent 
Persistent 
 
The Excel file will have information regarding: Randomization number, outcome of 
(Peri)pancreatic necrosis. Organ failure will be captured in accordance with section 7.7. 
 
7.10.2 Analysis 
No statistical tests will be performed. 
7.10.3 Presentation 
The Determinant Based Classification of Acute Pancreatitis will be presented using frequency 
tables. 
 
7.11 Secondary Endpoints - Pain Numeric Rating Scale (PNRS) 
7.11.1 Definition 
The mean daily Pain Numeric Rating Scale (PNRS) score will be calculated using. 


 Protocol Number: CM4620-201 
CTC Project Code: 188_18_2018 
 
Statistical Analysis Plan version 1.0 
 
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The absolute and percent change from baseline will be calculated. 
7.11.2 Analysis 
No statistical tests will be performed. 
7.11.3 Presentation 
The PNRS will be presented using summary statistics with graphs over time presenting the 
mean, absolute and percent change. 
 
7.12 Secondary Endpoints - Critical-Care Pain Observation Tool (CPOT) 
7.12.1 Definition 
Critical-Care Pain Observation Tool (CPOT) total score will be calculated from each individual 
item along with absolute and percent change. 


 Protocol Number: CM4620-201 
CTC Project Code: 188_18_2018 
 
Statistical Analysis Plan version 1.0 
 
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7.12.2 Analysis 
No statistical tests will be performed. 
7.12.3 Presentation 
The CPOT will be presented using summary statistics with graphs over time presenting the 
mean, absolute and percent change. 
 


 Protocol Number: CM4620-201 
CTC Project Code: 188_18_2018 
 
Statistical Analysis Plan version 1.0 
 
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7.13 Secondary Endpoints - Overall Survival 
7.13.1 Definition 
Overall Survival will be defined as 90 days survival. If a patient is alive at day 90 such patient will 
be censored. The overall survival time will be the time from randomization to either death or 
censored date (could be lost to follow up or day 90). 
The incidence of death will be calculated. 
7.13.2 Analysis 
No statistical tests will be performed. 
7.13.3 Presentation 
The incidence of death will be presented using listings. 
 
7.14 Secondary Endpoints – Hospitalization days 
7.14.1 Definition 
Total time in hospital is defined as (datetime of discharge from hospital – datetime of 
randomization). The time in intensive care unit will be calculated as time of first ICU visit until 
discharge from ICU unit. If no endpoint is recorded, time in hospital/ICU will be set to 30 days. If 
the patient died in hospital/ICU, the date of death (time 00:00 imputed if missing) will be used 
to calculate time in hospital/ICU.  
7.14.2 Analysis 
No statistical tests will be performed. 
7.14.3 Presentation 
Both the total number of hospital days and number of days at ICU will be presented using 
summary statistics. 
 
7.15 Discontinuation 
Patients who discontinue from IMP treatment will be tabulated. The reason for discontinuation 
will be given. For discontinuation due to AE, the AEs will be given. 
 
7.16 Interim Analysis 
Not applicable 
 
8 
CHANGES FROM THE CSP 
 
9 
STATISTICAL DELIVERABLES 
The following documents will be delivered: 
 
SAP 
 
Statistical analyses and summary tables 


 Protocol Number: CM4620-201 
CTC Project Code: 188_18_2018 
 
Statistical Analysis Plan version 1.0 
 
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10 SOFTWARE 
All statistical analyses will be performed using SAS Version 9.4 (SAS institute, Cary, NC). 
 
 


 Protocol Number: CM4620-201 
CTC Project Code: 188_18_2018 
 
Statistical Analysis Plan version 1.0 
 
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11 APPROVAL 
 
Issued by: 
 
 
______________________________  
_____________________ 
Fredrik Hansson, Director Biometrics 
 
Date (dd-Mmm-yyyy) 
CTC Representative 
 
 
 
 
 
Approved by: 
 
 
 
 
 
 
04-Apr-2019 
______________________________  
_____________________ 
Sudarshan Hebbar 
 
 
Date (dd-Mmm-yyyy) 
CalciMedica Representative