Clinical trial NCT03709342
Conditions: Acute Pancreatitis
Sponsor: CalciMedica, Inc.
Start date: 2019-01-06; Completion date: 2019-06-07
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This open-label study will evaluate the pharmacodynamic and pharmacokinetic profile of CM4620-IE in patients with acute pancreatitis. The first five (5) patients will receive ≤ 2.08 mg/kg of CM4620-IE by continuous IV infusion on Day 1. If necessary, up to an additional 4 patients may be treated at a different dose of CM4620-IE as determined by the obtained PK and PD data. The infusion of CM4620-IE will start within 12 hours from the time the patient or LAR provides informed consent.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: CM4620-IE
Intervention descriptions: intervention 1: single IV infusion on Day 1 over 4 hours

Protocol documents:
Prot_000.pdf: 
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CM4620-202 
A Pharmacodynamic and Pharmacokinetic Study of 
CM4620 Injectable Emulsion in 
Patients with Acute Pancreatitis 
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: 1.0 
Issue Date: September 25, 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 
26 Sept 2018 
26-Sep-2018


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SYNOPSIS 
Protocol Number: CM4620-202 
Protocol Title: 
A Pharmacodynamic and Pharmacokinetic Study of CM4620 Injectable 
Emulsion (CM4620-IE) in Patients with Acute Pancreatitis 
Sponsor: 
CalciMedica, Inc. 
505 Coast Blvd. South, Suite 202 
La Jolla, CA 92037 USA 
Study Phase: 
2 
Planned Number 
of Patients and 
Sites: 
Approximately 5 patients with acute pancreatitis will be dosed at 1 site. 
CM4620-IE Dose 
and Route of 
Administration: 
A single dose of CM4620-IE at ≤ 2.08 mg/kg will be administered on Day 
1 in 5 patients. If necessary, up to an additional 4 patients may be treated 
at a different dose of CM4620-IE as determined by the obtained PK and 
PD data.  All doses of CM4620-IE will be administered intravenously (IV) 
over 4 hours. 
Objectives: 
Primary: 
• To assess the change in IL-2 production by stimulated T-
lymphocytes ex vivo after a single dose of CM4620-IE in patients 
with acute pancreatitis 
Secondary: 
• To assess the safety and tolerability of a single dose of CM4620-IE 
in patients with acute pancreatitis 
• To determine the pharmacokinetic profile of CM4620-IE after a 
single dose in patients with acute pancreatitis 
• To assess changes in circulating levels of IL-6. 
Inclusion Criteria: Patients must meet all of the following criteria to be enrolled in the study: 
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 and/or serum amylase > 3 times the upper limit 
of normal (ULN); 
b. Characteristic findings of acute pancreatitis on abdominal imaging; 
2. Adults ≥ 18 years of age; 
3. A female patient of child-bearing potential who is sexually active with 
a male partner must be willing to practice acceptable methods of birth 


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control for 365 days after the last dose of CM4620-IE; 
4. 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; 
5. Willing and able to, or have a legal authorized representative (LAR) 
who is willing and able to, provide informed consent to participate, and 
cooperate with all aspects of the protocol. 
Exclusion 
Criteria: 
Patients with any of the following conditions or characteristics must be 
excluded from enrolling in the study: 
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 or may limit expected survival to < 6 months; 
2. Suspected presence of cholangitis in the judgment of the treating 
investigator; 
3. Any malignancy being treated with chemotherapy or immunotherapy; 
4. Any autoimmune disease being treated with immunosuppressive 
medication or immunotherapy (Section 5.3 for list of prohibited 
medications); 
5. History of: 
a. Chronic pancreatitis, pancreatic 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. Myocardial infarction, revascularization, cardiovascular accident 
(CVA) in the 30 days prior to Day 1; 
6. Current renal replacement therapy; 
7. Current known abuse of cocaine or methamphetamine; 
8. Known to be pregnant or are nursing; 
9. Participated in another study of an investigational drug or therapeutic 
medical device in the 30 days prior to Day 1; 
10. History of allergy to eggs or known hypersensitivity to any 
components of CM4620-IE; 
11. Prior treatment with CM4620-IE. 


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Study Design: 
This open-label study will evaluate the pharmacodynamic and 
pharmacokinetic profile of CM4620-IE in patients with acute pancreatitis.  
The first five (5) patients will receive ≤ 2.08 mg/kg of CM4620-IE by 
continuous IV infusion on Day 1. If necessary, up to an additional 4 
patients may be treated at a different dose of CM4620-IE as determined by 
the obtained PK and PD data.  The infusion of CM4620-IE will start 
within 12 hours from the time the patient or LAR provides informed 
consent.   
 
The decision to enroll additional patients will be made after CalciMedica 
reviews the available pharmacodynamic, pharmacokinetic, safety and 
tolerability data from the first 5 patients enrolled and discusses the data 
with the Principal Investigator.  
 
A study physician or appropriately trained delegate will perform in all 
patients enrolled in the study who remain hospitalized, selected safety 
assessments daily through Day 10 and every 48 hours from Day 12 until 
Day 30, or until discharge if occurring earlier. Patients discharged prior to 
Day 30 will be asked to return for a blood draw and SAE evaluation. 
Those patients who do not return will be contacted on Day 30 (± 2 days) to 
capture SAEs and any readmissions 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.  
Safety 
Assessments: 
Safety assessments will consist of: 
• Limited physical examinations 
• Vital sign measurements 
• Clinical laboratory measurements 
• Specified concomitant medications 
• Incidence, intensity and relationship of treatment-emergent adverse 
events (TEAEs) and serious adverse events (SAEs) 
Pharmacodynamic 
Assessment: 
Blood samples for the measurement of IL-2 production by stimulated T-
lymphocytes will be obtained prior to the administration of CM4620-IE, 
and after completion of CM4620-IE administration. Serum or plasma 
samples will also be collected at these times for the measurement of IL-6 
levels. 


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Pharmacokinetic 
Assessments: 
Plasma samples for bioanalytical assessment of CM4620 concentration 
will be obtained after the completion of CM4620-IE administration. 
Statistical 
Considerations 
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 ................................................................................................................................ 11 
List of Figures ............................................................................................................................... 11 
List of Terms and Abbreviations .................................................................................................. 12 
1 
INTRODUCTION ................................................................................................................. 14 
1.1 
Acute Pancreatitis ....................................................................................................... 14 
1.2 
Pathophysiology of Acute Pancreatitis ....................................................................... 15 
1.3 
Overview of CM4620 ................................................................................................. 17 
1.4 
Pre-Clinical Development of CM4620 ....................................................................... 17 
1.4.1 
Pre-Clinical Safety and Toxicology Studies .................................................. 17 
1.4.2 
Preclinical Efficacy Studies ........................................................................... 18 
1.5 
Clinical Development of CM4620-IE ......................................................................... 19 
1.6 
Rationale for the Study and Selected Doses ............................................................... 22 
2 
OBJECTIVES........................................................................................................................ 23 
2.1 
Primary Objective ....................................................................................................... 23 
2.2 
Secondary Objectives.................................................................................................. 23 
3 
INVESTIGATIONAL PLAN ............................................................................................... 24 
3.1 
Study Design ............................................................................................................... 24 
3.2 
End of Study ............................................................................................................... 24 
3.3 
Sponsor or Regulatory Agency Termination of the Study.......................................... 24 
4 
SELECTION OF PATIENTS ............................................................................................... 25 
4.1 
Inclusion Criteria ........................................................................................................ 25 
4.2 
Exclusion Criteria ....................................................................................................... 26 
5 
TREATMENT OF PATIENTS ............................................................................................. 27 
5.1 
Overview ..................................................................................................................... 27 
5.2 
Discharge Criteria ....................................................................................................... 27 
5.3 
Prohibited Medications ............................................................................................... 27 
5.4 
Compliance ................................................................................................................. 28 


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6 
PROCEDURES ..................................................................................................................... 29 
6.1 
Enrollment Procedures ................................................................................................ 29 
6.2 
Discontinuation and Withdrawal ................................................................................ 29 
7 
CM4620-IE MATERIALS AND MANAGEMENT ............................................................ 30 
7.1 
CM4620-IE Product Description ................................................................................ 30 
7.2 
CM4620-IE Storage .................................................................................................... 30 
7.3 
CM4620-IE Preparation .............................................................................................. 30 
7.4 
CM4620-IE Administration ........................................................................................ 31 
7.5 
Packaging and Labeling .............................................................................................. 31 
7.6 
Accountability, Handling and Disposal ...................................................................... 31 
8 
VISITS AND ASSESSMENTS ............................................................................................ 32 
8.1 
Screening..................................................................................................................... 32 
8.2 
Day 1 (-1 hour to <24 hours) ...................................................................................... 32 
8.3 
Day 2 (24 hours to <48 hours) .................................................................................... 33 
8.4 
Days 3-4 (48 hours to 72 hours) ................................................................................. 33 
8.5 
Day 5 (96 hours) ......................................................................................................... 33 
8.6 
Days 6 – 9 ................................................................................................................... 34 
8.7 
Day 10 ......................................................................................................................... 34 
8.8 
Days 12 – 30 ............................................................................................................... 35 
8.9 
Day 90 ......................................................................................................................... 35 
8.10 Study Assessments ...................................................................................................... 35 
8.10.1 Medical History ............................................................................................. 35 
8.10.2 Concomitant Medications .............................................................................. 36 
8.10.3 Physical Examination .................................................................................... 36 
8.10.4 Vital Signs ..................................................................................................... 36 
8.10.5 Pregnancy Testing ......................................................................................... 36 
8.10.6 Laboratory Analyses ...................................................................................... 36 
8.10.7 PD, PK and Biomarker analysis .................................................................... 36 
8.10.8 Pain Numeric Rating Scale (PNRS) .............................................................. 37 
8.10.9 Critical-Care Pain Observation Tool (CPOT) ............................................... 37 
9 
ADVERSE EVENTS ............................................................................................................ 38 
9.1 
Definition of Adverse Event ....................................................................................... 38 


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9.2 
Definition of Serious Adverse Event .......................................................................... 38 
9.3 
Eliciting Adverse Event Information .......................................................................... 39 
9.4 
Recording Adverse Events .......................................................................................... 39 
9.5 
Assessment of Relationship to CM4620-IE ................................................................ 40 
9.6 
Assessment of Severity ............................................................................................... 40 
9.7 
Reporting of Serious Adverse Events ......................................................................... 41 
9.8 
Suspected Pregnancy in a Woman of Childbearing Potential .................................... 42 
10 STATISTICAL ANALYSIS ................................................................................................. 43 
10.1 Sample Size ................................................................................................................. 43 
10.2 Study Assessments ...................................................................................................... 43 
10.3 Analysis Sets ............................................................................................................... 43 
10.4 Statistical Analyses Plan ............................................................................................. 44 
11 ADMINISTRATIVE CONSIDERATIONS ......................................................................... 45 
11.1 Electronic Case Report Forms .................................................................................... 45 
11.2 Monitoring of the Study .............................................................................................. 45 
11.3 Inspection of Records ................................................................................................. 45 
11.4 Study Record Retention .............................................................................................. 45 
11.5 Study Conduct: Good Clinical Practice and Declaration of Helsinki ......................... 45 
11.6 Responsibilities of the Investigator and the IRB/EC/REB ......................................... 46 
11.7 Confidentiality ............................................................................................................ 46 
11.8 Modification of the Protocol ....................................................................................... 46 
11.9 Informed Consent........................................................................................................ 47 
11.10 Protocol Violations and Deviations ............................................................................ 47 
11.11 Financial Disclosure.................................................................................................... 48 
11.12 Sponsor Obligations .................................................................................................... 48 
11.13 Investigator Documentation ........................................................................................ 48 
11.14 Clinical Study Insurance ............................................................................................. 49 
11.15 Use of Information ...................................................................................................... 49 
11.16 Publications ................................................................................................................. 49 
12 REFERENCES ...................................................................................................................... 50 
Appendix 1 
IAP/APA Summary of Recommendations ........................................................... 52 
Appendix 2 
Pain Numeric Rating Scale (PNRS) ..................................................................... 57 


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Appendix 3 
The Critical-Care Pain Observation Tool (CPOT) ............................................... 58 
Appendix 4 
Schedule of Events ................................................................................................ 59 
 
List of Tables 
Table 1 
SAD (CM4620-101) ................................................................................................... 20 
Table 2 
MAD (CM4620-102) .................................................................................................. 21 
Table 3 
CM4620-IE Product Information ................................................................................ 30 
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. ................. 16 
Figure 2. Sites of action of CM4620 in treating acute pancreatitis ............................................ 19 


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LIST OF TERMS AND ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
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 
mg 
milligram 


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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 
SAP 
Statistical analysis plan 
SOC 
Standard of care 
SOCE 
Store-operated calcium entry 
SOFA 
Sequential organ failure assessment 
SOP 
Standard operating procedures 
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. Severe acute pancreatitis is defined by 
the presence of persistent organ failure, moderately severe acute pancreatitis by either or 
transient organ failure or local or systemic complications, and mild acute pancreatitis by none of 
these features. 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 


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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 
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 synthesizing, 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 synthesizing 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 Ca2+ 
from ER 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 


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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). 
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 the high intracellular Ca2+ 
load, further promoting 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 relatively low residual drug levels in both MAD groups, in 
which plasma levels on Days 11-270 remained significantly lower (69-90% 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 365 days 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 


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further characterize the terminal phase and the prolonged period of residual drug level as well as 
recalculate the terminal half-life. There were no SAEs or AEs reported as moderate or severe in 
severity 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 and that body-weight also had a significant influence on volume of 
distribution. These features may be related to lower plasma AUC24h values in females versus 
males, and patients with higher body weights may have a lower AUC. The model was then used 
to identity the dosing regimens for the first and second phases of study CM4620-201, an open-
label dose-response study of CM4620 injectable emulsion in patients with acute pancreatitis and 
accompanying systemic inflammatory response syndrome that is currently enrolling patients. 
1.6 
Rationale for the Study and Selected Doses 
As mentioned above, an open-label study in patients with acute pancreatitis is currently being 
performed to further characterize the safety, efficacy and pharmacokinetic profile of a higher 
exposure of CM4620-IE than that obtained on Day 7 in the 5th group of the SAD and the 2nd 
group of the MAD. 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. 
The first dose level selected for the current pharmacodynamic and pharmacokinetic study 
(CM4620-202) comes from doses to be administered on Day 1 of study CM4620-201 (1.0 or 
2.08 mg/kg), the open label safety, efficacy and pharmacokinetic study that is currently active 
and screening patients. Doses of ≥1.0 mg/kg are projected to achieve blood levels of CM4620 at 
Tmax that will be inhibitory to CRAC channels and in an ex vivo whole blood assay of stimulated 
IL-2 release from T lymphocytes that depends on CRAC channel activity, thereby demonstrating 
pharmacological activity of CM4620 in blood.  It is hypothesized that with the proper dose 
regimen, pharmacological activity of CM4620 in blood will indicate potential for achieving 
efficacy in treating acute pancreatitis and accompanying SIRS. 


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2 
OBJECTIVES 
2.1 
Primary Objective 
• To assess the change in IL-2 production by stimulated T-lymphocytes ex vivo after a 
single dose of CM4620-IE in patients with acute pancreatitis. 
2.2 
Secondary Objectives 
• To assess the safety and tolerability of a single dose of CM4620-IE in patients with 
acute pancreatitis. 
• To determine the pharmacokinetic profile of CM4620-IE after a single dose in 
patients with acute pancreatitis. 
• To assess changes in circulating levels of IL-6. 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
This open-label, dose-response, study will evaluate the pharmacodynamic and pharmacokinetic 
profile of CM4620-IE in patients with acute pancreatitis. The first 5 patients will receive ≤2.08 
mg/kg of CM4620-IE by continuous IV infusion on Day 1. If necessary, up to an additional 4 
patients may be treated at a different dose of CM4620-IE determined by the obtained PK and PD 
data.  The infusion of CM4620-IE will start within 12 hours from the time the patient or LAR 
provides informed consent.   
 
The decision to enroll additional patients will be made after CalciMedica reviews the available 
pharmacodynamic, pharmacokinetic, safety and tolerability data from the first 5 patients enrolled 
and discusses the data with the Principal Investigator.  
 
A study physician or appropriately trained delegate will perform in all patients enrolled in the 
study who remain hospitalized, selected safety assessments daily through Day 10 and every 48 
hours from Day 12 until Day 30, or until discharge if occurring earlier. Patients discharged prior 
to Day 30 will be asked to return on Day 30 to provide a blood draw for PK and PD 
determinations and to record any SAEs and readmissions to the hospital.  For patients that cannot 
return to the hospital on Day 30, they will be contacted on Day 30 (± 2 days) to capture SAEs 
and any readmissions to the hospital. Patients will also be contacted on Day 90 (± 7 days) to 
assess mortality. 
CalciMedica may submit modifications to the protocol to change the planned doses, the dosing 
schedule, the infusion time, the number of sites in the study and the total number of patients 
enrolled in the study for safety and/or tolerability considerations. 
3.2 
End of Study 
The End of Study is considered the date on which the last patient 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 enrolled 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 and/or serum amylase > 3 times the upper limit of normal (ULN); 
b. Characteristic findings of acute pancreatitis on abdominal imaging; 
2. Adults ≥ 18 years of age; 
3. 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; 
4. 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; 
5. Willing and able to, or have a LAR who is willing and able to, provide informed consent 
to participate and 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 or may limit 
expected survival to < 6 months; 
2. Suspected presence of cholangitis, in the judgment of the treating investigator; 
3. Any malignancy being treated with chemotherapy or immunotherapy; 
4. Any autoimmune disease being treated with immunosuppressive medication or 
immunotherapy (Section 5.3 for list of prohibited medications); 
5. History of: 
a. Chronic pancreatitis, pancreatic 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. Myocardial infarction, revascularization, cardiovascular accident (CVA) in the 30 
days prior to Day 1; 
6. Current renal replacement therapy; 
7. Current known abuse of cocaine or methamphetamine; 
8. Known to be pregnant or are nursing; 
9. Participated in another study of an investigational drug or therapeutic medical device in 
the 30 days prior to Day 1; 
10. History of allergy to eggs or known hypersensitivity to any components of CM4620-IE. 
11. Prior treatment with CM4620-IE. 


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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. 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.  
A summary of recommendations from the 2013 IAP/APA evidence based guidelines for the 
management of acute pancreatitis is listed in Appendix 1. 
5.2 
Discharge Criteria 
All patients should be discharged from the hospital using criteria consistent with local standard 
of care (SOC). The suggested criteria for discharging patients with acute pancreatitis from the 
hospital are: 
• Abdominal pain has resolved 
• Normal oral diet is tolerated 
• There is no clinical or laboratory evidence of an infection or continued inflammation 
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 
• Biologics/Monoclonals: abatacept, adalimumab, alemtuzumab, anakinra, basilizimab, 
belimumab, bevacizumab, brodalumab, canakinumab, certolizumab, cetuximab, 
daclizumab, eculizumab, etanercept, golimumab, infliximab, interferon, ixekizumab, 


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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 
entered into 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 
Enrollment Procedures 
Patients will be sequentially enrolled to receive CM4620-IE in addition to supportive care 
consistent with the 2013 IAP/APA evidence-based guidelines for the management of acute 
pancreatitis.  
6.2 
Discontinuation and Withdrawal 
Discontinuation refers to the patient or PI discontinuing the administration of CM4620-IE before 
the 4-hour infusion has been completed. 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 the administration of CM4620-IE. 
The PI must discontinue the administration of CM4620-IE if the patient is discovered to have 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 18 months and is being 
evaluated for longer periods in ongoing studies. Sites will be notified if any meaningful 
decrement in stability is discovered. 
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 
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 


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Pharmacy Manual. The Pharmacy Manual will also contain tables detailing the Volume to Be 
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 IV over 4 hours at a constant rate of infusion. 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 from 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 timing of the 
infusion and the rate of infusion based on its review of the safety and tolerability data. 
CalciMedica will discuss with the PI 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 (cGMP) 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 the patient or LAR provides informed consent 
After informed consent is obtained, the following procedures are to be performed: 
• Record the time of the onset of abdominal pain 
• 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/or 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 
If the patient satisfies all of the inclusion criteria and none of the exclusion criteria, enroll the 
patient in the study and immediately proceed to Day 1. 
8.2 
Day 1 (-1 hour to <24 hours) 
Perform the following procedures immediately prior to infusion of CM4620-IE: 
• Record vital signs 
• Record specified concomitant medications 
• Record patient’s pain using the PNRS (Pain Numeric Rating Scale) 
• Assess pain using the CPOT (Critical-care Pain Observation Tool) 
• Draw a blood sample for CBC, platelets and differential and chemistry profile - analyze 
at local lab 
• Draw a blood sample for IL-6 assay – send to testing lab  
• Draw blood sample for PD assay 1 hour (± 30 minutes) prior to administration of 
CM4620-IE-send to testing lab 
• Start the administration of CM4620-IE within 12 hours from the time the patient or LAR 
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• Draw a blood sample(s) for PD and PK assays 30 minutes (± 15 minutes) after 
completing the administration of CM4620-IE - send to testing labs 
• Draw a blood sample for serum biomarker assay (IL-6) 30 minutes (± 15 minutes) after 
completing the administration of CM4620-IE - send sample for IL-6 analysis to testing 
lab 
• Perform AE/SAE assessment after completing the administration of CM4620-IE 
8.3 
Day 2 (24 hours to <48 hours) 
At 24 hours (±1 hour) from the start of administration of CM4620-IE: 
• Record vital signs 
• Record specified concomitant medications 
• Draw a blood sample for CBC, differential and platelets, chemistry profile - analyze at 
local lab 
• Record patient’s pain using the PNRS 
• Assess pain using the CPOT 
• Perform AE/SAE assessment 
• Draw a blood sample(s) for PD and PK assays 24 hours (±1 hour) from the start of the 
administration of CM4620-IE - send to testing labs 
• Draw a blood sample for serum biomarker assay (IL-6) 24 hours (±1 hour) from the start 
of the administration of CM4620-IE - send sample for IL-6 analysis to testing lab 
8.4 
Days 3-4 (48 hours to 72 hours) 
For all patients who remain hospitalized, at 48 hours (±1 hour) and 72 hours (±1 hour) from the 
start of administration of CM4620-IE: 
• Record vital signs 
• Record specified concomitant medications 
• Record patient’s pain using the PNRS 
• Assess pain using the CPOT 
• Perform AE/SAE assessment 
8.5 
Day 5 (96 hours) 
For all patients who remain hospitalized, at 96 hours (±1 hour) from the start of administration of 
CM4620-IE: 


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• Record vital signs 
• Record specified concomitant medications 
• Record patient’s pain using the PNRS 
• Assess pain using the CPOT 
• Perform AE/SAE assessment 
• Draw a blood sample for CBC, differential and platelets, chemistry profile - analyze at 
local lab 
• Draw a blood sample(s) for PD and PK assays 96 hours (±1 hour) from the start of the 
administration of CM4620-IE - send to testing labs 
• Draw a blood sample for serum biomarker assay (IL-6) 96 hours (±1 hour) from the start 
of the administration of CM4620-IE - send sample for IL-6 analysis to testing lab. 
8.6 
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 start of administration of CM4620-IE: 
• Record vital signs 
• Record specified concomitant medications 
• Record patient’s pain using the PNRS 
• Assess pain using the CPOT 
• Perform AE/SAE assessment 
8.7 
Day 10 
For all patients who remain hospitalized, at 216 hours (±1 hour) from the start of administration 
of CM4620-IE: 
• Record vital signs 
• Record specified concomitant medications 
• Perform limited physical examination 
• Draw a blood sample for CBC, differential and platelets, chemistry profile - analyze at 
local lab 
• Draw a blood sample(s) for PD and PK assays 216 hours (±1 hour) from the start of the 
administration of CM4620-IE - send to testing labs 
• Draw a blood sample for serum biomarker assay (IL-6) 216 hours (±1 hour) from the 
start of the administration of CM4620-IE - send sample for IL-6 analysis to testing lab 


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• Record patient’s pain using the PNRS 
• Assess pain using the CPOT 
• Perform AE/SAE assessment 
If the patient is discharged before Day 10, Day 10 procedures should be performed prior to 
discharge. 
8.8 
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 
• If the patient has been discharged from the hospital and returns for a follow-up visit on 
Day 30 (± 7 days), on Day 30 (± 7 days) draw a blood sample(s) for PD and PK assays - 
send to testing labs.  Also, perform an SAE assessment and determine if patient has been 
readmitted to the hospital. If the patient has been discharged from the hospital and does 
not plan to return for a follow-up visit, contact the patient on Day 30 (± 7 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) 
8.9 
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) 
8.10 
Study Assessments 
8.10.1 
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 
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8.10.2 
Concomitant Medications 
Concomitant medications will be recorded from Day 1 through Day 10, or until discharge if 
occurring earlier. The name, dose and frequency of all analgesics, antipyretics and antimicrobials 
that the patients are taking will be recorded as well as vasopressor(s) and highest dose of 
vasopressors. If a prohibited medication has been administered, it will be recorded. The time of 
administration of the individual doses, and the route of administration will also be recorded. 
Generic names should be used when possible. 
8.10.3 
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. 
8.10.4 
Vital Signs 
The recorded vital signs must include the patient’s current temperature, heart rate (beats per 
minute), systolic and diastolic blood pressures, and the respiratory rate (breaths per minute).  
8.10.5 
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 
enrolled and receive CM4620-IE. 
8.10.6 
Laboratory Analyses 
On Days 1, 2, 5 and on Day 10, or until discharge if occurring earlier, a CBC, differential, 
platelet count, and chemistry profile will be drawn once. The chemistry profile sent to the local 
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 PI or treating physician will order all additional laboratory testing necessary for the 
management of the patient and analysis will be performed at the local laboratory.  
8.10.7 
PD, PK and Biomarker analysis 
On Day 1, blood samples for PD analysis will be obtained 1 hour (± 30 minutes) prior to 
administration of CM4620-IE.  Blood samples for IL-6 will also be drawn 1 hour prior to 
administration of CM4620-IE. Blood samples for PD and PK analysis, plus IL-6, will be 
obtained 30 minutes (± 15 minutes) after completing the administration of CM4620-IE and at 24 


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hours (± 1 hour) from the start of the administration of CM4620-IE. In patients who remain 
hospitalized at Day 5 and Day 10, blood samples for PD and PK analysis, plus IL-6, will be 
obtained 96 (± 1 hour) and 216 hours (± 1 hour), respectively, from the start of the 
administration of CM4620-IE. The date and time of the blood samples (both the absolute time 
and the time before or after administration of CM4620-IE) should be recorded. A blood sample 
for PD and PK analysis will also be drawn at the Day 30 visit. All blood samples will be sent to 
the appropriate testing labs. Results will not be provided to the PI or treating physician. 
8.10.8 
Pain Numeric Rating Scale (PNRS) 
In patients who are able to self-report their pain, the Pain Numeric Rating Scale (PNRS, 
Appendix 2) 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 should also be recorded. 
8.10.9 
Critical-Care Pain Observation Tool (CPOT) 
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 3). 


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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 meet 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 you were last contacted?” 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 upon initiation of study drug dosing on Day 1. All conditions 
present before initiation of study treatment on Day 1, 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 


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emergency) because the pre-existing condition worsens, the worsening condition should be 
captured as an AE. 
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 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 PI 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 initiation of study drug treatment on Day 1 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 PI deems the event to be 
chronic or the patient to be stable. CalciMedica or its designee may contact the PI 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 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 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 PI 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 PI 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 PI 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 PI 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 PI 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 5 patients, with the possibility of enrolling 4 more patients. The 
sample size was selected based on practical considerations to initially evaluate the 
pharmacodynamic and pharmacokinetic profile of CM4620-IE in patients with acute pancreatitis. 
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, specified concomitant medications and incidence, intensity and 
relationship of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) 
• Pharmacodynamic assessment will include IL-2 production by stimulated T-lymphocytes 
• 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 receive one 
complete administration of CM4620-IE 
• 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 enrolled 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. 


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11 
ADMINISTRATIVE CONSIDERATIONS 
11.1 
Electronic Case Report Forms 
The study will use a data capture system that is 21 CFR Part 11 compliant to electronically 
capture data for all screened and enrolled 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 the 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 


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conduct all aspects of this study in accordance with all national, state and local laws or 
regulations. 
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 LAR) 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 
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The revision number and date of the amendment will be recorded on the title page of the 
protocol. 
The PI is responsible for informing the IRB/EC/REB of all problems involving risks to patients. 
In case of urgent safety measures, CalciMedica or its designee will immediately notify the PI 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.  
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 
The PI and sub-investigators are required to provide financial disclosure information prior to 
starting the study. In addition, the PI 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 PI, 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 
REFERENCES 
Balthazar EJ. Acute pancreatitis: assessment of severity with clinical and CT evaluation. 
Radiology. 2002;223(3);603-13. https://doi.org/10.1148/radiol.2233010680. 
Banks PA, Bollen TL, Dervenis C. Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG, Vege SS, 
Acute Pancreatitis Classification Working Group Classification of acute pancreatitis—2012: 
revision of the Atlanta classification and definitions by international consensus. Gut. 
2013;62:102-11. 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, Ca2+ Stores and Acute Pancreatitis; a step closer to 
therapy? Cell Calcium. Apr 30 2016;pii: S0143-4160(16)30053-7. 
doi:10.1016/j.ceca.2016.04.007. [Epub ahead of print]. 
Dellinger EP, Forsmark CE, Layer P. Determinant-based classification of acute pancreatitis 
severity: an international multidisciplinary consultation. Ann Surg. 2012;256:875-80. 
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. American Journal of Critical Care. 2006;15(4):420-27. 
Gerasimenko JV, Gryshchenko O, Ferdek PE, Stapleton E, Hébert TO, Bychkova S, Peng S, 
Begge M, Gerasimenko OV, Petersen OH. Ca2+ release-activated Ca2+ channel blockade as a 
potential tool in antipancreatitis therapy. Proc Natl Acad Sci USA. 2013;110(32):13186-191. 
doi: www.pnas.org/cgi/doi/10.1073/pnas.1300910110. 
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease 
classification system. Critical care medicine. 1985;13(10):818-29. 
Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet. 2015 Jul 4;386(9988):85-96. 
doi: 10.1016/S0140-6736(14)60649-8. Epub 2015 Jan 21. 
Lindkvist B, Appelros S, Manjer J, Berglund G, Borgström A. A prospective cohort study of 
smoking in acute pancreatitis. Pancreatology. 2008;8:63-70. 
doi: https://doi.org/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. 13 October 2009;19(19):1648-53. 
doi: 10.1016/j.cub.2009.07.072. Epub 2009 Sep 17. 
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. American Journal of Roentgenology. 
2004;183(5):1261-65. doi: 10.2214/ajr.183.5.1831261. 
Muallem S, Schoeffield MS, Fimmel CJ. Agonist-sensitive calcium pool in the pancreatic acinar 
cell. I. Permeability properties. Am J Physiol. 1988.255:221-28. 


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Petersen OH, Gerasimenko OV, Gerasimenko JV. Pathobiology of acute pancreatitis: focus on 
intracellular calcium and calmodulin. F1000 Med Rep. 2011;3:15. doi: 10.3410/M3-15. 
Epub 2011 Aug 1. 
Petersen OH, Sutton R. Ca2+ signalling and pancreatitis: effects of alcohol, bile and coffee. 
Trends in Pharmaceutical Sciences. 2006;27(2):113-20. 
Phillip V, Steiner JM, Algül H. Early phase of acute pancreatitis: Assessment and management. 
World J Gastrointest Pathophysiol. August 15, 2014;5(3):158-68. doi: 10.4291/wjgp.v5.i3.158. 
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, 
Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS. The third international consensus 
definitions for sepsis and septic shock (sepsis-3). Jama. 2016;315(8);801-10. 
doi: 10.1001/jama.2016.0287. 
Singh VK, Bollen TL, Wu BU, Repas K, Maurer R, Yu S, Mortele KJ, Conwell DL, Banks PA. 
An assessment of the severity of interstitial pancreatitis. Clin Gastroenterol Hepatol. 
2011;9:1098-103. doi: 10.1016/j.cgh.2011.08.026. 
Tolstrup JS, Kristiansen L, Becker U, Grønbæk M. Smoking and risk of acute and chronic 
pancreatitis among women and men: a population-based cohort study. Arch Intern Med. 
2009;169:603-9. doi: 10.1001/archinternmed.2008.601. 
Wen L, Voronina S, Javed, MA, Awais M, Szatmary P, Latawiec D, Chvanov M, Collier D, 
Huang W, Barrett J, Begg M. Inhibitors of ORAI1 prevent cytosolic calcium-associated injury 
of human pancreatic acinar cells and acute pancreatitis in 3 mouse models. Gastroenterology. 
2015;149(2):481-92. 
Werner J, Feuerbach S, Uhl W, Büchler MW. Management of acute pancreatitis: from surgery to 
interventional intensive care. Gut. 2005.54:426-36. doi: http://dx.doi.org/10.1136/gut.2003.035907. 
Whitcomb DC. Acute Pancreatitis. N Engl J Med. 2006;354:2142-50. 
doi: 10.1056/NEJMcp054958. 
Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines 
for the management of acute pancreatitis. Pancreatology. 2013;13:e1-e15. 
doi: http://dx.doi.org/10.1016/j.pan.2013.07.063. 
 


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Appendix 1 
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 
is to perform axial FS-T2 and FS-T1 scanning before and after intravenous gadolinium contrast 


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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 > 0.5 ml/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 
case of surgical decompression, the retroperitoneal cavity and the omental bursa should be left 


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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 2 
Pain Numeric Rating Scale (PNRS) 
 


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Appendix 3 
The Critical-Care Pain Observation Tool (CPOT) 
Adapted from Gélinas, 2006 
 


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Appendix 4 
Schedule of Events 
 
Screen 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Days 6, 7 
Days 8, 9 
Day10 g 
Days 12-28 a Day 30 b 
Day 90 c 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics & Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior & Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Physical Examination (limited) 
X 
 
 
 
 
 
 
 
X 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test for WOCBP 
X 
 
 
 
 
 
 
 
 
 
 
 
Amylase or Lipase 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample for Serum Chemistries 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
Blood Sample for CBC, Diff & Platelets 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
Blood Sample for PD Analysis d 
 
X 
X 
 
 
X 
 
 
X 
 
X 
 
Blood Sample for PK Analysis e 
 
X 
X 
 
 
X 
 
 
X 
 
X 
 
Blood Sample for IL-6 f 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
Assess Pain 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
AE/SAE Evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CM4620-IE Administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
                                                 
a 
Safety and tolerability assessment after Day 10 will be done every 48 hours until Day 30 or until discharge, whichever occurs first 
b Day 30 visit (± 7 days): for patients who have been discharged prior to Day 30, for a SAE evaluation and blood draw. If the patient does not return for the clinic visit, a telephone call to the patient will be made 
for an SAE evaluation. 
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 On Days 1 and 2, blood samples for PD analysis will be obtained 1 hour (± 30 minutes) prior to starting the administration of CM4620-IE, ± 30 minutes (± 15 minutes) after completing the administration of 
CM4620-IE, and 24 hours (± 1 hour) from the start of the administration of CM4620-IE. In patients hospitalized at Day 5 and 10, a PD blood sample will be drawn; if discharged earlier obtain a PD blood 
sample at the time of discharge. 
e 
On Days 1 and 2, plasma samples for PK analysis will be obtained ± 30 minutes (± 15 minutes) after completing the administration of CM4620-IE and 24 hours (± 1 hour) from the start of the administration of 
CM4620-IE. In patients hospitalized at Day 5 and 10, a PK plasma sample will be obtained; if discharged earlier obtain a PK plasma sample at the time of discharge. 
f 
On Day 1, serum or plasma samples for IL-6 will be obtained 1-hour prior to the administration of CM4620-IE, ± 30 minutes (± 15 minutes) after completing the administration of CM4620-IE, and 24 hours (± 
1 hour) from the start of the administration of CM4620-IE. In patients hospitalized at Day 5 and 10, a serum or plasma sample for IL-6 will be drawn 96 (± 1 hour) and 216 hours (± 1 hour), respectively, from 
the start of the administration of CM4620-IE. 
g Day 10 procedures will be performed if the patient is discharged prior to Day 10  

SAP_001.pdf: 
Protocol Number: CM4620-202 
CTC Project Code: 211_53_2018 
 
 
Template ID: BM004Temp01_01_SP 
 
 
 
 
 
 
 
CONFIDENTIAL 
Statistical Analysis Plan (SAP) 
___________________________________________________________ 
 
Sponsor: 
CalciMedica through EMAS 
Study code: 
CM4620-202 
Study title: 
A Pharmacodynamic and Pharmacokinetic 
Study of CM4620 Injectable Emulsion in 
Patients with Acute Pancreatitis 
Date: 
Draft 1 – 14May2019 
Final – 29May2019 
 
 
 


 Protocol Number: CM4620-201 
CTC Project Code: 188_18_2018 
 
Statistical Analysis Plan version 1.0 
 
 2 (9) 
TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS ...................................................................................................................... 4 
2 
INTRODUCTION ........................................................................................................................................ 5 
3 
CLINICAL STUDY DETAILS .................................................................................................................... 5 
3.1 
Clinical Study Objectives.......................................................................................................... 5 
3.1.1 
Primary objective ............................................................................................................. 5 
3.1.2 
Primary endpoint ............................................................................................................. 5 
3.1.3 
Secondary objectives ....................................................................................................... 5 
3.1.4 
Secondary endpoints ....................................................................................................... 5 
3.2 
Clinical Study Design ................................................................................................................ 5 
3.3 
Number of Subjects ................................................................................................................. 6 
3.4 
Methods of Assigning Subject to IMP ..................................................................................... 6 
3.5 
Blinding .................................................................................................................................... 6 
4 
STATISTICAL AND ANALYTICAL PLANS........................................................................................... 6 
4.1 
Sample Size Justification .......................................................................................................... 6 
4.2 
Definition of Analysis Sets ....................................................................................................... 6 
4.2.1 
Full Analysis Set ............................................................................................................... 6 
4.2.2 
Safety Analysis Set ........................................................................................................... 6 
4.2.3 
Per Protocol Set ............................................................................................................... 6 
4.2.4 
Use of analysis set ........................................................................................................... 6 
4.3 
Definition of Baseline .............................................................................................................. 6 
4.4 
Summary Statistics .................................................................................................................. 7 
4.5 
Significance Level..................................................................................................................... 7 
4.6 
Multiple Comparisons/Multiplicity ......................................................................................... 7 
4.7 
Handling of Drop-outs, Missing Data and Outliers .................................................................. 7 
4.8 
Adjustment for Covariates ...................................................................................................... 7 
4.9 
Multicenter Studies ................................................................................................................. 7 
4.10 
Examination of Subgroups....................................................................................................... 7 
4.11 
Blind Review ............................................................................................................................ 7 
5 
SUBJECTS .................................................................................................................................................... 7 
5.1 
Subject Disposition .................................................................................................................. 7 
5.2 
Baseline Characteristics and Demographics ............................................................................ 7 
6 
TREATMENT INFORMATION AND EXTENT OF EXPOSURE ....................................................... 7 
6.1 
Active Treatment ..................................................................................................................... 7 
6.2 
Prior and Concomitant Medications ....................................................................................... 7 
7 
STATISTICAL METHODOLOGY ............................................................................................................ 7 


 Protocol Number: CM4620-201 
CTC Project Code: 188_18_2018 
 
Statistical Analysis Plan version 1.0 
 
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7.1 
Secondary endpoint(s) ............................................................................................................ 7 
7.1.1 
Adverse events ................................................................................................................ 7 
7.1.2 
Vital signs ......................................................................................................................... 7 
7.1.3 
Days in hospital ............................................................................................................... 8 
7.1.4 
Safety laboratory ............................................................................................................. 8 
7.2 
Discontinuation ....................................................................................................................... 8 
7.3 
Interim Analysis ....................................................................................................................... 8 
8 
CHANGES FROM THE CSP ...................................................................................................................... 8 
9 
STATISTICAL DELIVERABLES .............................................................................................................. 8 
10 
SOFTWARE ............................................................................................................................................ 8 
11 
APPROVAL ............................................................................................................................................. 9 
 
 
 


 Protocol Number: CM4620-201 
CTC Project Code: 188_18_2018 
 
Statistical Analysis Plan version 1.0 
 
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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 
 
 


 Protocol Number: CM4620-201 
CTC Project Code: 188_18_2018 
 
Statistical Analysis Plan version 1.0 
 
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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 CM4620-202. Any 
changes from the final CSP are given in Section 8. This needs to be approved and signed prior to 
database lock. 
 
This SAP will not cover the analysis of IL-6 and pharmacokinetic analyses- 
 
3 
CLINICAL STUDY DETAILS 
3.1 Clinical Study Objectives 
3.1.1 Primary objective 
N/A 
3.1.2 Primary endpoint 
N/A 
3.1.3 Secondary objectives 
To assess the safety and tolerability of a single dose of CM4620-IE in patients with acute 
pancreatitis. 
3.1.4 Secondary endpoints 
The secondary efficacy endpoints are: 
 
Adverse events including SAE  
 
Vital signs 
 
Days in hospital 
 
Safety laboratory 
 
3.2 Clinical Study Design 
This open-label, dose-response, study will evaluate the pharmacodynamic and pharmacokinetic 
profile of CM4620-IE in patients with acute pancreatitis. The first 5 patients will receive ≤2.08 
mg/kg of CM4620-IE by continuous IV infusion on Day 1. If necessary, up to an additional 4 
patients may be treated at a different dose of CM4620-IE determined by the obtained PK and PD 
data.  The infusion of CM4620-IE will start within 12 hours from the time the patient or LAR 
provides informed consent.   
 
The decision to enroll additional patients will be made after CalciMedica reviews the available 
pharmacodynamic, pharmacokinetic, safety and tolerability data from the first 5 patients 
enrolled and discusses the data with the Principal Investigator.  


 Protocol Number: CM4620-201 
CTC Project Code: 188_18_2018 
 
Statistical Analysis Plan version 1.0 
 
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A study physician or appropriately trained delegate will perform in all patients enrolled in the 
study who remain hospitalized, selected safety assessments daily through Day 10 and every 48 
hours from Day 12 until Day 30, or until discharge if occurring earlier. Patients discharged prior 
to Day 30 will be asked to return on Day 30 to provide a blood draw for PK and PD 
determinations and to record any SAEs and readmissions to the hospital.  For patients that 
cannot return to the hospital on Day 30, they will be contacted on Day 30 (± 2 days) to capture 
SAEs and any readmissions to the hospital. Patients will also be contacted on Day 90 (± 7 days) 
to assess mortality. 
CalciMedica may submit modifications to the protocol to change the planned doses, the dosing 
schedule, the infusion time, the number of sites in the study and the total number of patients 
enrolled in the study for safety and/or tolerability considerations. 
 
3.3 Number of Subjects 
7 subjects 
3.4 Methods of Assigning Subject to IMP 
N/A 
3.5 Blinding 
N/A 
4 
STATISTICAL AND ANALYTICAL PLANS 
4.1 Sample Size Justification 
This open-label study will enroll 5 patients, with the possibility of enrolling 4 more patients. The 
sample size was selected based on practical considerations to initially evaluate the 
pharmacodynamic and pharmacokinetic profile of CM4620-IE in patients with acute pancreatitis. 
This study is not powered for analysis of study data with inferential statistics. 
4.2 Definition of Analysis Sets 
4.2.1 Full Analysis Set  
The full analysis set includes all patients with acute pancreatitis who receive one complete 
administration of CM4620-IE. 
4.2.2 Safety Analysis Set  
The safety population includes all patients who receive any amount of study drug treatment 
4.2.3 Per Protocol Set 
N/A. 
4.2.4 Use of analysis set 
Safety analysis set will be used in the analyses described below. The FAS population will be used 
for IL-6 and pharmacokinetics. 
4.3 Definition of Baseline 
Baseline measurement is defined as the latest measurement prior to first dose of IMP. 


 Protocol Number: CM4620-201 
CTC Project Code: 188_18_2018 
 
Statistical Analysis Plan version 1.0 
 
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4.4 Summary Statistics 
No summary statistics will be used. 
4.5 Significance Level 
N/A 
4.6 Multiple Comparisons/Multiplicity 
N/A 
4.7 Handling of Drop-outs, Missing Data and Outliers  
N/A 
4.8 Adjustment for Covariates 
N/A 
4.9 Multicenter Studies 
N/A 
4.10 Examination of Subgroups 
N/A 
4.11 Blind Review 
N/A. 
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 listings 
6 
TREATMENT INFORMATION AND EXTENT OF EXPOSURE 
6.1 Active Treatment 
N/A 
6.2 Prior and Concomitant Medications 
Prior and concomitant medication data will be listed and by ATC code. Prior and concomitant 
medications will be coded according to the World Health Organization (WHO Drug Dictionary) 
classification system. 
7 
STATISTICAL METHODOLOGY 
7.1 Secondary endpoint(s) 
7.1.1 Adverse events 
The adverse events will be presented using listings. 
7.1.2 Vital signs 
The vital signs parameters will be presented using listings together with absolute and relative 
change from baseline. 


 Protocol Number: CM4620-201 
CTC Project Code: 188_18_2018 
 
Statistical Analysis Plan version 1.0 
 
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7.1.3 Days in hospital 
Days in hospital will be presented using listings. 
7.1.4 Safety laboratory 
The safety laboratory parameters will be presented using listings together with absolute and 
relative change from baseline. 
 
7.2 Discontinuation 
Patients who discontinue from IMP treatment will be listed. The reason for discontinuation will 
be given. For discontinuation due to AE, the AEs will be given. 
 
7.3 Interim Analysis 
N/A 
 
8 
CHANGES FROM THE CSP 
 
9 
STATISTICAL DELIVERABLES 
The following documents will be delivered: 
 
SAP 
 
Listings 
 
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: 
 
 
______________________________  
_____________________ 
Sudarshan Hebbar 
 
 
Date (dd-Mmm-yyyy) 
CalciMedica Representative 
 
 
02-Jul-2019