A Study of Auxora in Patients With Acute Pancreatitis and Accompanying SIRS

Study Overview
=================
Brief Summary
-----------------
Approximately 216 patients with acute pancreatitis and accompanying SIRS will be randomized at approximately 30 sites. Patients will be randomly assigned to either Auxora at one of three dose levels or one of three placebo volumes to maintain the double-blind. Study drug infusions will occur every 24 hours for three consecutive days for a total of three infusions. Patients will remain hospitalized as per standard of care and once discharged will be asked to complete a daily meal diary and return for a Day 30 safety assessment. It is recommended that patients randomized in the study should not be discharged from the hospital until solid food is tolerated, abdominal pain has resolved or been adequately controlled, and there is no clinical evidence of infection necessitating continued hospitalization.

Detailed Description
-----------------
This double blind, randomized, placebo-controlled study will evaluate the efficacy, safety, and tolerability of three different dose levels of Auxora in patients with acute pancreatitis and accompanying SIRS. Approximately 216 patients will be randomized 1:1:1:1 into one of 4 groups using a computer generated randomization scheme accessed through an interactive voice/web response system (IXRS). Randomization will be first stratified by gender (male or female) and then by risk for organ failure in the gender subgroups (higher or lower). Higher risk for organ failure is defined by the presence of both an elevated hematocrit (HCT ≥44% for men or ≥40% for women) and hypoxemia (imputed PaO2/FiO2 ≤360). Lower risk for organ failure is defined by the absence of either or both an elevated hematocrit and hypoxemia. The PaO2/FiO2 will be determined using an arterial blood gas or imputed using pulse oximetry. All patients will have received a Screening CECT of the abdomen/pancreas before being randomized into the study. CECTs performed as standard of care may be used as the Screening CECT but must have been performed in the 24 hours before Consent or after Consent and before Randomization. The Start of First Infusion of Study Drug (SFISD) should occur within 8 hours of the patient or LAR providing informed consent. Patients randomized to Group 1 will receive 2.0 mg/kg of Auxora intravenously every 24 hours (±1 hour) for a total of three doses. Patients randomized to Group 2 will receive 1.0 mg/kg of Auxora intravenously every 24 hours (±1 hour) for a total of three doses. Patients randomized to Group 3 will receive 0.5 mg/kg of Auxora intravenously every 24 hours (±1 hour) for a total of three doses. Patients randomized to Group 4 will receive emulsion without any active pharmaceutical ingredient. Patients in Group 4 will receive one of three randomly assigned dose volumes, 1.25 mL/kg, 0.625 mL/kg, or 0.3125 mL/kg, which will be administered intravenously every 24 hours (±1 hour) for a total of three doses. The dosing will be based on actual body weight obtained at the time of hospitalization or screening for the study. As described in the pharmacy manual, the upper limit of the volume of Auxora and volume of Placebo that will be administered will be 156.25 mL. The sponsor, investigators and patients will be blinded to the assigned group. In the event of a medical emergency, investigators will be able to receive the treatment assignment if required to provide optimal care of the patient. For all 4 groups, a study physician or appropriately trained delegate will perform assessments at screening, at the baseline assessment, immediately prior to the SFISD, and then every 24 hours until 240 hours after the SFISD, or until discharge if earlier. If patients remain hospitalized at Day 12, assessments will then be performed every 48 hours starting on Day 12 until Day 28, or until discharge if earlier. Patients discharged from the hospital before Day 25 will return at Day 30 (+5 days) to perform the Day 30 assessments. If patients are discharged on Days 25-29, the Day 30 assessments may be performed prior to discharge. Patients will receive another CECT of the abdomen/pancreas at the Day 30 (±5 days) visit. All CECTs performed as standard of care after randomization and before the Day 30 CECT will also be captured. A blinded central reader will read the Screening, Day 30, and any standard of care CECTs obtained between randomization and the Day 30 visit. Patients will complete the modified American Neurogastroenterology and Motility Society Gastrointestinal Cardinal Symptom Index Daily Diary (mGCSI-DD) worksheet at the baseline assessment, at 96 hours, 168hours, Day 14 and Day 21 (for patients who remain hospitalized on these days), on the day of discharge, and daily at bedtime after discharge until the Day 30 visit. Patients who are discharged on Days 25-29 will not complete the mGCSI worksheet after discharge. It is recommended that all patients randomized in the study should receive care consistent with the 2018 American Gastroenterological Association (AGA) Institute Technical Review of the Initial Medical Management of Acute Pancreatitis. Patients should receive local standard of care (SOC) for the management of other medical conditions. In patients with acute pancreatitis, the AGA strongly recommends early oral feeding (within 24 hours) rather than keeping the patient nil per mouth (Nil per Os, NPO). Patients randomized into the study, therefore, will be offered a low fat, ≥500-calorie solid meal at each mealtime after the infusion of the first dose of study drug if alert and not on mechanical ventilation, or if not NPO for a planned surgey/medical procedure, or if not NPO because of an acute medical condition. If the patient does not wish to eat the solid meal when offered or is unable to tolerate the solid meal, they should then be offered a liquid meal. The same approach should occur at each subsequent mealtime. When patients eat a solid meal, it should be recorded if they ate ≥50% of the meal and if they either vomited or experienced an increase in abdominal pain in the two hours after eating a meal. It is also recommended that all patients randomized in the study should not be discharged from the hospital until solid food is tolerated, abdominal pain has resolved or been adequately controlled, and there is no clinical evidence of infection. Tolerating solid food is defined as eating ≥50% of a low fat, ≥500-calorie solid meal without an increase in abdominal pain or vomiting. If the patient is not tolerating either solid or liquid meals, tube feedings should be considered. All protocol required laboratory testing, except biomarker and PK samples, will be performed at the local laboratory. Results from the biomarkers and PK blood samples collected as part of the protocol and being tested at a central lab will not be available to assist the PI or treating physician in managing the patient.

Official Title
-----------------
A Randomized, Double-Blind, Placebo Controlled Dose-Ranging Study of Auxora in Patients With Acute Pancreatitis and Accompanying Systemic Inflammatory Response Syndrome

Conditions
-----------------
Acute Pancreatitis, Systemic Inflammatory Response Syndrome

Intervention / Treatment
-----------------
* Drug: CM-4620 Injectable Emulsion or CM-4620-IE
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All of the following must be met for a patient to be randomized into the study: The diagnosis of acute pancreatitis has been established by the presence of abdominal pain consistent with acute pancreatitis together with at least 1 of the following 2 criteria: Serum lipase > 3 times the upper limit of normal (ULN); Characteristic findings of acute pancreatitis on abdominal imaging; The diagnosis of SIRS has been established by the presence of at least two of the following four criteria: Temperature < 36°C or > 38°C; Heart rate > 90 beats/minute; Respiratory rate >20 breaths/minute or arterial carbon dioxide tension (PaCO2) <32 mmHg; White blood cell count (WBC) >12,000 mm3, or <4,000 mm3, or > 10% immature (band) forms; At least one of the following criteria is also present: A peripancreatic fluid collection or a pleural effusion on a contrast-enhanced computed tomography (CECT) performed in the 24 hours before Consent or after Consent and before Randomization; Abdominal examination documenting either abdominal guarding or rebound tenderness; Hematocrit ≥44% for men or ≥40% for women; The patient is ≥ 18 years of age; Lack of pancreatic necrosis, pancreatic calcifications, pancreatic pseudocysts and no evidence for previous necrosectomy or pancreatic surgery identified by CECT performed in the 24 hours before Consent or after Consent and before Randomization; A female patient of childbearing potential who is sexually active with a male partner is willing to practice acceptable methods of birth control for 180 days after the last dose of study drug. A female patient must not attempt to become pregnant for 180 days; A male patient who is sexually active with a female partner of childbearing potential is willing to practice acceptable methods of birth control for 180 days after the last dose of study drug. A male patient must not donate sperm for 180 days; The patient is willing and able to, or has a legal authorized representative (LAR) who is willing and able to, provide informed consent to participate, and to cooperate with all aspects of the protocol. Exclusion Criteria: Patients with any of the following conditions or characteristics must be excluded from randomizing: Expected survival <6 months; Suspected presence of cholangitis in the judgment of the treating physician; The patient has a known history of: Organ or hematologic transplant; HIV, hepatitis B, or hepatitis C infection; Chronic pancreatitis; Current treatment with: Chemotherapy; Immunosuppressive medications or immunotherapy Pancreatic enzyme replacement therapy; Hemodialysis or Peritoneal Dialysis; The patient is known to be pregnant or is nursing; The patient has participated in another study of an investigational drug or therapeutic medical device in the 30 days before randomization; Allergy to eggs or known hypersensitivity to any components of study drug.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 2.0 mg/kg (1.25 mL/kg)<br>administered intravenously over 4 hours at a constant rate of infusion. They will be administered every 24 hours (±1 hours) for three consecutive days for a total of 3 doses. | Drug: CM-4620 Injectable Emulsion or CM-4620-IE<br>* Auxora is to be administered as an IV infusion and is supplied as a translucent, white to yellowish colored, sterile, non-pyrogenic emulsion containing 1.6 mg/mL of the active pharmaceutical ingredient 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.<br>* Other names: Auxora;|
| Active Comparator: 1.0 mg/kg (0.625 mL/kg)<br>administered intravenously over 4 hours at a constant rate of infusion. They will be administered every 24 hours (±1 hours) for three consecutive days for a total of 3 doses. | Drug: CM-4620 Injectable Emulsion or CM-4620-IE<br>* Auxora is to be administered as an IV infusion and is supplied as a translucent, white to yellowish colored, sterile, non-pyrogenic emulsion containing 1.6 mg/mL of the active pharmaceutical ingredient 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.<br>* Other names: Auxora;|
| Active Comparator: 0.5 mg/kg (0.3125 mL/kg)<br>administered intravenously over 4 hours at a constant rate of infusion. They will be administered every 24 hours (±1 hours) for three consecutive days for a total of 3 doses. | Drug: CM-4620 Injectable Emulsion or CM-4620-IE<br>* Auxora is to be administered as an IV infusion and is supplied as a translucent, white to yellowish colored, sterile, non-pyrogenic emulsion containing 1.6 mg/mL of the active pharmaceutical ingredient 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.<br>* Other names: Auxora;|
| Placebo Comparator: Placebo (1.25, 0.625, or 0.3125 mL/kg)<br>patients randomized to placebo will receive one of three following volumes (1.25 mL/kg, 0.625 mL/kg, and 0.3125 mL/kg. although three volumes - all patients randomized to placebo will be analyzed together as one arm. administered intravenously over 4 hours at a constant rate of infusion. They will be administered every 24 hours (±1 hours) for three consecutive days for a total of 3 doses. | Other: Placebo<br>* Matching Placebo is to be administered as an IV infusion and is supplied as a translucent, white to yellowish, sterile, non-pyrogenic emulsion carrier containing no active pharmaceutical ingredient. Placebo is supplied as an 80 mL fill in a 100 mL single-use vial. Placebo contains the same ingredients as Auxora except that it does not contain CM4620.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to solid food tolerance | Defined as the number of hours from the date and time of the start of the first infusion of study (SFISD) for the patient to the date and time the patient receives a solid meal that is tolerated | from start of first infusion of study drug (SFISD) to day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Solid food tolerance |  | from SFISD to 48 hours, 72 hours and 96 hours and at time of hospital discharge | 
| Time to medically indicated discharge |  | from start of first infusion of study drug and through time of hospital discharge or through Day 30, whichever occurs first | 
| Length of stay in the hospital |  | from admission date into the hospital until discharge date from the hospital | 
| Length of stay in the ICU for patients admitted to the ICU |  | from admission into ICU until discharge from ICU | 
| Re-hospitalization for acute pancreatitis by Day 30 |  | time from initial date of hospital discharge through date of re-hospitalization through day 30 | 
| Change in severity of acute pancreatitis by CTSI score from screening to Day 30 |  | from informed consent through day 30 | 
| Development of pancreatic necrosis ≥30% and >50% |  | from enrollment CECT through Day 30 CECT | 
| The persistence of SIRS ≥48 hours after the SFISD |  | from SFISD through day 30 | 
| Incidence, severity, and duration of organ failure |  | from enrollment and through day 30 | 
| Mortality by Day 30 |  | from randomization and through day 30 | 
| Change in pain score |  | from enrollment through day 30 | 
| Change in opioid use |  | from enrollment through day 30 |