Acute Pancreatitis, Systemic Inflammatory Response Syndrome
Conditions
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 surgery/medical procedure, or if not NPO because of an acute medical condition. If the patient does not wish to eat the solid meal when offered or is unable to tolerate the solid meal, they should then be offered a liquid meal. The same approach should occur at each subsequent mealtime. 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.
Interventions
DRUGCM-4620 Injectable Emulsion or CM-4620-IE
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.
OTHERPlacebo
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.
Sponsors
CalciMedica, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Matching placebo
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
All of the following must be met for a patient to be randomized into the study: 1. 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: 1. Serum lipase \> 3 times the upper limit of normal (ULN); 2. Characteristic findings of acute pancreatitis on abdominal imaging; 2. The diagnosis of SIRS has been established by the presence of at least two of the following four criteria: 1. Temperature \< 36°C or \> 38°C; 2. Heart rate \> 90 beats/minute; 3. Respiratory rate \>20 breaths/minute or arterial carbon dioxide tension (PaCO2) \<32 mmHg; 4. White blood cell count (WBC) \>12,000 mm3, or \<4,000 mm3, or \> 10% immature (band) forms; 3. At least one of the following criteria is also present: 1. 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; 2. Abdominal examination documenting either abdominal guarding or rebound tenderness; 3. Hematocrit ≥44% for men or ≥40% for women; 4. The patient is ≥ 18 years of age; 5. Lack of pancreatic necrosis, pancreatic calcifications, pancreatic pseudocysts and no evidence for previous necrosectomy or pancreatic surgery identified by CECT performed in the 24 hours before Consent or after Consent and before Randomization; 6. A female patient of childbearing potential who is sexually active with a male partner is willing to practice acceptable methods of birth control for 180 days after the last dose of study drug. A female patient must not attempt to become pregnant for 180 days; 7. A male patient who is sexually active with a female partner of childbearing potential is willing to practice acceptable methods of birth control for 180 days after the last dose of study drug. A male patient must not donate sperm for 180 days; 8. The patient is willing and able to, or has a legal authorized representative (LAR) who is willing and able to, provide informed consent to participate, and to cooperate with all aspects of the protocol.
Exclusion criteria
Patients with any of the following conditions or characteristics must be excluded from randomizing: 1. Expected survival \<6 months; 2. Suspected presence of cholangitis in the judgment of the treating physician; 3. The patient has a known history of: 1. Organ or hematologic transplant; 2. HIV, hepatitis B, or hepatitis C infection; 3. Chronic pancreatitis; 4. Current treatment with: 1. Chemotherapy; 2. Immunosuppressive medications or immunotherapy 3. Pancreatic enzyme replacement therapy; 4. Hemodialysis or Peritoneal Dialysis; 5. The patient is known to be pregnant or is nursing; 6. The patient has participated in another study of an investigational drug or therapeutic medical device in the 30 days before randomization; 7. Allergy to eggs or known hypersensitivity to any components of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to Solid Food Tolerance, With gMCP Modeling Analysis for Dose-response Relationship | from start of first infusion of study drug (SFISD) through day 30 | Time to Solid Food Tolerance (TSFT): Number of hours from date/time of SFISD to date/time patient receives a solid meal that is tolerated, defined as eating \>/=50% of a low fat \>/= 500-calorie solid meal w/o increase in abdominal pain or vomiting within 2 hours of mealtime. If patient was discharged w/o tolerating solid food, the daily record of the modified ANMS Gastrointestinal Cardinal Symptom Index Daily Diary (mGCSI-DD) at or after hospital discharge was used to calculate TSFT. For these patients, TSFT date/time was considered to be 8am on the first of 3 consecutive days where the following criteria were met in mGCSI-DD: no vomiting, no or mild nausea, no or mild inability to finish a normal sized meal, no or mild abdominal pain. gMCP-Mod: Generalized Multiple Comparisons and Modeling--3 steps: 1) Hazard ratio (dose vs placebo) using stratified Cox regression w/ stratification by sex and hematocrit (high/low). 2) Multiple contrast test. 3) Find best-fit dose-response model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With New Onset Severe Respiratory Failure, With gMCP Modeling Analysis for Dose-response Relationship | from enrollment and through day 30 | Analysis of patients without respiratory failure at the time of randomization (defined as a P/F ratio ≤300 measured by an arterial blood gas or imputed from pulse oximetry) who later developed severe respiratory failure during the course of the study. |
| Incidence, Severity, and Duration of Organ Failure | from enrollment and through day 30 | The incidence, severity and duration of organ failure was defined by the development of severe respiratory failure or severe renal failure or severe cardiac failure. The proportion of patients who developed each type of organ failure, or multi-organ failure (more than 1 organ failure), was analyzed. |
| Solid Food Tolerance | from SFISD to 48 hours, 72 hours and 96 hours and at time of hospital discharge (up to 30 days after SFISD) | Number (and percentage) of patients who tolerated solid food at 48hrs, 72hrs, and 96hrs from start of first infusion of study drug, as well as at time of first discharge from hospital |
| Time to Medically Indicated Discharge | from start of first infusion of study drug through time of hospital discharge or through Day 30, whichever occurs first | The time (in hours) to medically indicated discharge, defined as the number of days from the SFISD to the first date of meeting the criteria below: * the patient tolerated solid food, as defined by the main analytical approach; and * abdominal pain was controlled or resolved, which was defined by a reduction in pain, as assessed by the PNRS scale, of ≥50% from the peak level in the first 24 hours and no use of opioids; and * no clinical evidence of an infection requiring continued hospitalization. Kaplan-Meier (K-M) estimates of median time to medically indicated discharge are shown. |
| Length of Stay in the Hospital | from admission date into the hospital until discharge date from the hospital | Number of days in the hospital during the first 30 Days of the Study from the SFISD (start of first infusion of study drug) while still alive, for any reason. Includes ICU stay and readmissions. The number of days in the hospital before the patient's death was used in the analysis.(Note: there was only 1 patient death in this study, in the 1.0 mg/kg Auxora group) |
| Re-hospitalization for Acute Pancreatitis by Day 30 | time from initial date of hospital discharge through date of re-hospitalization through day 30 | The proportion of patients who were re-hospitalized for either acute pancreatitis, or the development of pancreatic necrosis/necrotizing pancreatitis through the Day 30 visit. |
| Change in Severity of Acute Pancreatitis by CTSI Score From Screening to Day 30 | From informed consent through day 30 | Independent reviewers performed a blinded central review of Contrast Enhanced Computed Tomography (CECT) imaging data, or MRI imaging data, obtained at the Screening and Day 30 visits to assess the Computed Tomography Severity Index (CTSI). Review was performed by two independent radiologists (primary review) using a consensus methodology. The CTSI scoring uses a combination of Balthazar score grading of pancreatitis (A-E) and grading the extent of pancreatic necrosis (none, ≤30%, \>30-50%, or \>50%) to designate AP as mild, moderate, or severe. Proportion of patients with moderate or severe AP by CTSI score at baseline who became mild AP at Day 30, and the proportion of patients with mild AP by CTSI at baseline who had moderate or severe AP at Day 30 were analyzed. |
| Development of Pancreatic Necrosis ≥30% and >50% | from enrollment CECT through Day 30 CECT | Development of pancreatic necrosis ≥30% and \>50% in patients who had no pancreatic necrosis at screening (Note: There were no patients with pancreatic necrosis at screening in any of the treatment groups.) |
| The Persistence of SIRS ≥48 Hours After the SFISD | from SFISD through day 30 | The proportion of patients who developed persistence of SIRS ≥48 Hours after the SFISD analyzed through Day 30. If the patient was discharged before 48 Hours after the SFISD, the last available post-treatment data was used to define the SIRS status at 48 hours after the SFISD based on the LOCF method. |
| Mortality by Day 30 | from randomization and through day 30 | Mortality was assessed from randomization through Day 30 |
| Change in Pain Score | from enrollment through day 30 | Mean change in Pain Numeric Rating Score (PNRS) from baseline (time of screening). In patients who were able to self-report their pain, the PNRS was used to grade the severity of the abdominal pain. Patients were asked, "On a scale of 0 to 10, with 0 being no pain at all and 10 being the worst pain imaginable, how would you rate your pain RIGHT NOW." It was also recorded if an opioid analgesic had been given in the 2 hours prior to the PNRS determination. |
Countries
India, United States
Contacts
STUDY_DIRECTORSudarshan Hebbar, MD
CalciMedica, Inc.
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) High dose Auxora, administered intravenously over 4 hours at a constant rate of infusion. Infusions were administered every 24 hours (±1 hour) for three consecutive days for a total of 3 doses. | 53 |
| Auxora 1.0 mg/kg (0.625 mL/kg) Medium dose Auxora, administered intravenously over 4 hours at a constant rate of infusion. Infusions were administered every 24 hours (±1 hour) for three consecutive days for a total of 3 doses. | 56 |
| Auxora 0.5 mg/kg (0.3125 mL/kg) Low dose Auxora, administered intravenously over 4 hours at a constant rate of infusion. Infusions were administered every 24 hours (±1 hour) for three consecutive days for a total of 3 doses. | 52 |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) Patients randomized to placebo received one of three following volumes (1.25 mL/kg, 0.625 mL/kg, and 0.3125 mL/kg. Although patients are randomly assigned to the three volumes, all patients randomized to placebo are analyzed together as one arm. Placebo was administered intravenously over 4 hours at a constant rate of infusion. Infusions were administered every 24 hours (±1 hours) for three consecutive days for a total of 3 doses. | 53 |
| Total | 214 |
Baseline characteristics
| Characteristic | Total | Placebo (1.25, 0.625, or 0.3125 mL/kg) | Auxora 0.5 mg/kg (0.3125 mL/kg) | Auxora 1.0 mg/kg (0.625 mL/kg) | Auxora 2.0 mg/kg (1.25 mL/kg) |
|---|---|---|---|---|---|
| Abdominal Guarding or Rebound | 154 Participants | 37 Participants | 35 Participants | 44 Participants | 38 Participants |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 35 Participants | 6 Participants | 12 Participants | 12 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 179 Participants | 47 Participants | 40 Participants | 44 Participants | 48 Participants |
| Age, Continuous | 46.26 years STANDARD_DEVIATION 15.943 | 44.79 years STANDARD_DEVIATION 15.181 | 49.23 years STANDARD_DEVIATION 16.131 | 47.41 years STANDARD_DEVIATION 16.876 | 43.58 years STANDARD_DEVIATION 15.311 |
| Balthazar score D or E | 145 Participants | 35 Participants | 38 Participants | 36 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 45 Participants | 13 Participants | 14 Participants | 8 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 165 Participants | 39 Participants | 38 Participants | 46 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants |
| Etiology Alcohol | 91 Participants | 18 Participants | 22 Participants | 25 Participants | 26 Participants |
| Etiology Biliary | 43 Participants | 14 Participants | 10 Participants | 11 Participants | 8 Participants |
| Etiology Drug Induced | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Etiology Hypertriglyceridemia | 22 Participants | 9 Participants | 5 Participants | 4 Participants | 4 Participants |
| Etiology Other | 16 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants |
| Etiology Surgery/Trauma | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Etiology Unknown | 39 Participants | 8 Participants | 10 Participants | 11 Participants | 10 Participants |
| High Hematocrit (>/= 44 males; >/= 40 females) | 92 Participants | 20 Participants | 24 Participants | 25 Participants | 23 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 69 Participants | 20 Participants | 16 Participants | 17 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 39 Participants | 8 Participants | 8 Participants | 10 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 20 Participants | 8 Participants | 6 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 84 Participants | 15 Participants | 22 Participants | 26 Participants | 21 Participants |
| Region of Enrollment India | 64 participants | 17 participants | 15 participants | 16 participants | 16 participants |
| Region of Enrollment United States | 150 participants | 36 participants | 37 participants | 40 participants | 37 participants |
| Sex: Female, Male Female | 83 Participants | 20 Participants | 20 Participants | 23 Participants | 20 Participants |
| Sex: Female, Male Male | 131 Participants | 33 Participants | 32 Participants | 33 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 1 / 56 | 0 / 52 | 0 / 53 |
| other Total, other adverse events | 22 / 53 | 32 / 56 | 26 / 52 | 23 / 53 |
| serious Total, serious adverse events | 8 / 53 | 12 / 56 | 13 / 52 | 6 / 53 |
Outcome results
Primary
Median Time to Solid Food Tolerance, With gMCP Modeling Analysis for Dose-response Relationship
Time to Solid Food Tolerance (TSFT): Number of hours from date/time of SFISD to date/time patient receives a solid meal that is tolerated, defined as eating \>/=50% of a low fat \>/= 500-calorie solid meal w/o increase in abdominal pain or vomiting within 2 hours of mealtime. If patient was discharged w/o tolerating solid food, the daily record of the modified ANMS Gastrointestinal Cardinal Symptom Index Daily Diary (mGCSI-DD) at or after hospital discharge was used to calculate TSFT. For these patients, TSFT date/time was considered to be 8am on the first of 3 consecutive days where the following criteria were met in mGCSI-DD: no vomiting, no or mild nausea, no or mild inability to finish a normal sized meal, no or mild abdominal pain. gMCP-Mod: Generalized Multiple Comparisons and Modeling--3 steps: 1) Hazard ratio (dose vs placebo) using stratified Cox regression w/ stratification by sex and hematocrit (high/low). 2) Multiple contrast test. 3) Find best-fit dose-response model.
Time frame: from start of first infusion of study drug (SFISD) through day 30
Population: Analysis for all treated patients and the high hematocrit subgroup are presented.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Median Time to Solid Food Tolerance, With gMCP Modeling Analysis for Dose-response Relationship | All Patients | 67.0 Hours |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Median Time to Solid Food Tolerance, With gMCP Modeling Analysis for Dose-response Relationship | High Hematocrit subgroup | 67.0 Hours |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Median Time to Solid Food Tolerance, With gMCP Modeling Analysis for Dose-response Relationship | High Hematocrit subgroup | 64.0 Hours |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Median Time to Solid Food Tolerance, With gMCP Modeling Analysis for Dose-response Relationship | All Patients | 64.0 Hours |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Median Time to Solid Food Tolerance, With gMCP Modeling Analysis for Dose-response Relationship | All Patients | 78.0 Hours |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Median Time to Solid Food Tolerance, With gMCP Modeling Analysis for Dose-response Relationship | High Hematocrit subgroup | 78.0 Hours |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Median Time to Solid Food Tolerance, With gMCP Modeling Analysis for Dose-response Relationship | All Patients | 66.0 Hours |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Median Time to Solid Food Tolerance, With gMCP Modeling Analysis for Dose-response Relationship | High Hematocrit subgroup | 113.5 Hours |
Comparison: The purpose of this analysis is to determine whether a dose-response relationship exists, with multiple possible models (Emax and sigEmax) being tested. gMCP-Mod analysis (Generalized Multiple Comparisons and Modeling) was performed in 3 steps as described in the SAP: 1) Hazard ratio (each dose vs placebo) using stratified Cox regression w/ stratification by sex and hematocrit (high/low HCT). 2) Multiple contrast test. 3) Find best-fit dose-response model.~Emax model analysis is shown here.p-value: 0.3184Mixed Models Analysis
Comparison: The purpose of this analysis is to determine whether a dose-response relationship exists, with multiple possible models (Emax and sigEmax) being tested. gMCP-Mod analysis (Generalized Multiple Comparisons and Modeling) was performed in 3 steps as described in the SAP: 1) Hazard ratio (each dose vs placebo) using stratified Cox regression w/ stratification by sex and hematocrit (high/low HCT). 2) Multiple contrast test. 3) Find best-fit dose-response model.~Emax model analysis is shown here.p-value: 0.3184Mixed Models Analysis
Comparison: The purpose of this analysis is to determine whether a dose-response relationship exists, with multiple possible models (Emax and sigEmax) being tested. gMCP-Mod analysis (Generalized Multiple Comparisons and Modeling) was performed in 3 steps as described in the SAP: 1) Hazard ratio (each dose vs placebo) using stratified Cox regression w/ stratification by sex and hematocrit (high/low HCT). 2) Multiple contrast test. 3) Find best-fit dose-response model.~Emax model analysis is shown here.p-value: 0.3184Mixed Models Analysis
Comparison: The purpose of this analysis is to determine whether a dose-response relationship exists, with multiple possible models (Emax and sigEmax) being tested. gMCP-Mod analysis (Generalized Multiple Comparisons and Modeling) was performed in 3 steps as described in the SAP: 1) Hazard ratio (each dose vs placebo) using stratified Cox regression w/ stratification by sex and hematocrit (high/low HCT). 2) Multiple contrast test. 3) Find best-fit dose-response model.~sigEmax model analysis is shown here.p-value: 0.2265Mixed Models Analysis
Comparison: The purpose of this analysis is to determine whether a dose-response relationship exists, with multiple possible models (Emax and sigEmax) being tested. gMCP-Mod analysis (Generalized Multiple Comparisons and Modeling) was performed in 3 steps as described in the SAP: 1) Hazard ratio (each dose vs placebo) using stratified Cox regression w/ stratification by sex and hematocrit (high/low HCT). 2) Multiple contrast test. 3) Find best-fit dose-response model.~sigEmax model analysis is shown here.p-value: 0.2265Mixed Models Analysis
Comparison: The purpose of this analysis is to determine whether a dose-response relationship exists, with multiple possible models (Emax and sigEmax) being tested. gMCP-Mod analysis (Generalized Multiple Comparisons and Modeling) was performed in 3 steps as described in the SAP: 1) Hazard ratio (each dose vs placebo) using stratified Cox regression w/ stratification by sex and hematocrit (high/low HCT). 2) Multiple contrast test. 3) Find best-fit dose-response model.~sigEmax model analysis is shown here.p-value: 0.2265Mixed Models Analysis
Comparison: The purpose of this analysis is to determine whether a dose-response relationship exists for only the subset of patients with high HCT. Multiple possible models (Emax and sigEmax) were tested. gMCP-Mod (Generalized Multiple Comparisons \& Modeling) analysis was performed in 3 steps as described in the SAP: 1) Hazard ratio (each dose vs placebo) using stratified Cox regression, stratification by sex 2) Multiple contrast test 3) Find best-fit dose-response model. Emax model analysis is shown here.p-value: 0.0764Mixed Models Analysis
Comparison: The purpose of this analysis is to determine whether a dose-response relationship exists for only the subset of patients with high HCT. Multiple possible models (Emax and sigEmax) were tested. gMCP-Mod (Generalized Multiple Comparisons \& Modeling) analysis was performed in 3 steps as described in the SAP: 1) Hazard ratio (each dose vs placebo) using stratified Cox regression, stratification by sex 2) Multiple contrast test 3) Find best-fit dose-response model. Emax model analysis is shown here.p-value: 0.0764Mixed Models Analysis
Comparison: The purpose of this analysis is to determine whether a dose-response relationship exists for only the subset of patients with high HCT. Multiple possible models (Emax and sigEmax) were tested. gMCP-Mod (Generalized Multiple Comparisons \& Modeling) analysis was performed in 3 steps as described in the SAP: 1) Hazard ratio (each dose vs placebo) using stratified Cox regression, stratification by sex 2) Multiple contrast test 3) Find best-fit dose-response model. Emax model analysis is shown here.p-value: 0.0764Mixed Models Analysis
Comparison: The purpose of this analysis is to determine whether a dose-response relationship exists for the subset of patients with high HCT. Multiple possible models (Emax and sigEmax) were tested. gMCP-Mod (Generalized Multiple Comparisons \& Modeling) analysis was performed in 3 steps as described in the SAP: 1) Hazard ratio (each dose vs placebo) using stratified Cox regression, stratification by sex 2) Multiple contrast test 3) Find best-fit dose-response model. sigEmax model analysis is shown here.p-value: 0.0574Mixed Models Analysis
Comparison: The purpose of this analysis is to determine whether a dose-response relationship exists for the subset of patients with high HCT. Multiple possible models (Emax and sigEmax) were tested. gMCP-Mod (Generalized Multiple Comparisons \& Modeling) analysis was performed in 3 steps as described in the SAP: 1) Hazard ratio (each dose vs placebo) using stratified Cox regression, stratification by sex 2) Multiple contrast test 3) Find best-fit dose-response model. sigEmax model analysis is shown here.p-value: 0.0574Mixed Models Analysis
Comparison: The purpose of this analysis is to determine whether a dose-response relationship exists for the subset of patients with high HCT. Multiple possible models (Emax and sigEmax) were tested. gMCP-Mod (Generalized Multiple Comparisons \& Modeling) analysis was performed in 3 steps as described in the SAP: 1) Hazard ratio (each dose vs placebo) using stratified Cox regression, stratification by sex 2) Multiple contrast test 3) Find best-fit dose-response model. sigEmax model analysis is shown here.p-value: 0.0574Mixed Models Analysis
Secondary
Change in Pain Score
Mean change in Pain Numeric Rating Score (PNRS) from baseline (time of screening). In patients who were able to self-report their pain, the PNRS was used to grade the severity of the abdominal pain. Patients were asked, On a scale of 0 to 10, with 0 being no pain at all and 10 being the worst pain imaginable, how would you rate your pain RIGHT NOW. It was also recorded if an opioid analgesic had been given in the 2 hours prior to the PNRS determination.
Time frame: from enrollment through day 30
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Change in Pain Score | Change from Baseline at 96hrs | -4.6 score on a scale | Standard Deviation 3.26 |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Change in Pain Score | Change from Baseline at 72hrs | -4.1 score on a scale | Standard Deviation 3.49 |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Change in Pain Score | Change from Baseline at 48hrs | -3.3 score on a scale | Standard Deviation 3.33 |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Change in Pain Score | Change from Baseline at 72hrs | -3.8 score on a scale | Standard Deviation 3.18 |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Change in Pain Score | Change from Baseline at 96hrs | -4.5 score on a scale | Standard Deviation 3.87 |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Change in Pain Score | Change from Baseline at 48hrs | -3.2 score on a scale | Standard Deviation 2.98 |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Change in Pain Score | Change from Baseline at 72hrs | -3.8 score on a scale | Standard Deviation 3.71 |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Change in Pain Score | Change from Baseline at 48hrs | -3.2 score on a scale | Standard Deviation 3.22 |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Change in Pain Score | Change from Baseline at 96hrs | -3.1 score on a scale | Standard Deviation 3.21 |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Change in Pain Score | Change from Baseline at 96hrs | -3.6 score on a scale | Standard Deviation 2.29 |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Change in Pain Score | Change from Baseline at 72hrs | -3.7 score on a scale | Standard Deviation 3.18 |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Change in Pain Score | Change from Baseline at 48hrs | -3.1 score on a scale | Standard Deviation 3.1 |
Secondary
Change in Severity of Acute Pancreatitis by CTSI Score From Screening to Day 30
Independent reviewers performed a blinded central review of Contrast Enhanced Computed Tomography (CECT) imaging data, or MRI imaging data, obtained at the Screening and Day 30 visits to assess the Computed Tomography Severity Index (CTSI). Review was performed by two independent radiologists (primary review) using a consensus methodology. The CTSI scoring uses a combination of Balthazar score grading of pancreatitis (A-E) and grading the extent of pancreatic necrosis (none, ≤30%, \>30-50%, or \>50%) to designate AP as mild, moderate, or severe. Proportion of patients with moderate or severe AP by CTSI score at baseline who became mild AP at Day 30, and the proportion of patients with mild AP by CTSI at baseline who had moderate or severe AP at Day 30 were analyzed.
Time frame: From informed consent through day 30
Population: Patients were divided into two subgroups for this analysis: those with Moderate or Severe AP by CTSI score at baseline, and those with Mild AP by CTSI score at baseline. Analysis only includes subjects with non-missing Screening and Day 30 Visit (or post-treatment unscheduled visit) CTCE reading results.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Change in Severity of Acute Pancreatitis by CTSI Score From Screening to Day 30 | Patients with Moderate or Severe AP at baseline who had Mild AP at Day 30 (by CTSI score) | 10 Participants |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Change in Severity of Acute Pancreatitis by CTSI Score From Screening to Day 30 | Patients with Mild AP at baseline who had Moderate or Severe AP at Day 30 (by CTSI score) | 0 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Change in Severity of Acute Pancreatitis by CTSI Score From Screening to Day 30 | Patients with Moderate or Severe AP at baseline who had Mild AP at Day 30 (by CTSI score) | 8 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Change in Severity of Acute Pancreatitis by CTSI Score From Screening to Day 30 | Patients with Mild AP at baseline who had Moderate or Severe AP at Day 30 (by CTSI score) | 2 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Change in Severity of Acute Pancreatitis by CTSI Score From Screening to Day 30 | Patients with Mild AP at baseline who had Moderate or Severe AP at Day 30 (by CTSI score) | 2 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Change in Severity of Acute Pancreatitis by CTSI Score From Screening to Day 30 | Patients with Moderate or Severe AP at baseline who had Mild AP at Day 30 (by CTSI score) | 12 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Change in Severity of Acute Pancreatitis by CTSI Score From Screening to Day 30 | Patients with Moderate or Severe AP at baseline who had Mild AP at Day 30 (by CTSI score) | 14 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Change in Severity of Acute Pancreatitis by CTSI Score From Screening to Day 30 | Patients with Mild AP at baseline who had Moderate or Severe AP at Day 30 (by CTSI score) | 0 Participants |
Secondary
Development of Pancreatic Necrosis ≥30% and >50%
Development of pancreatic necrosis ≥30% and \>50% in patients who had no pancreatic necrosis at screening (Note: There were no patients with pancreatic necrosis at screening in any of the treatment groups.)
Time frame: from enrollment CECT through Day 30 CECT
Population: Only subjects with non-missing Screening and Day 30 Visit (or post-treatment unscheduled visit) CTCE reading results were analyzed
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Development of Pancreatic Necrosis ≥30% and >50% | Pancreatic Necrosis >50% | 1 Participants |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Development of Pancreatic Necrosis ≥30% and >50% | Pancreatic Necrosis 30% to 50% | 0 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Development of Pancreatic Necrosis ≥30% and >50% | Pancreatic Necrosis 30% to 50% | 0 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Development of Pancreatic Necrosis ≥30% and >50% | Pancreatic Necrosis >50% | 1 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Development of Pancreatic Necrosis ≥30% and >50% | Pancreatic Necrosis >50% | 1 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Development of Pancreatic Necrosis ≥30% and >50% | Pancreatic Necrosis 30% to 50% | 1 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Development of Pancreatic Necrosis ≥30% and >50% | Pancreatic Necrosis >50% | 0 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Development of Pancreatic Necrosis ≥30% and >50% | Pancreatic Necrosis 30% to 50% | 0 Participants |
Secondary
Incidence, Severity, and Duration of Organ Failure
The incidence, severity and duration of organ failure was defined by the development of severe respiratory failure or severe renal failure or severe cardiac failure. The proportion of patients who developed each type of organ failure, or multi-organ failure (more than 1 organ failure), was analyzed.
Time frame: from enrollment and through day 30
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Any severe organ failure | 2 Participants |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Severe respiratory failure | 2 Participants |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Severe renal failure | 0 Participants |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Severe cardiac failure | 1 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Severe cardiac failure | 1 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Severe renal failure | 1 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Severe respiratory failure | 2 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Any severe organ failure | 2 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Severe renal failure | 2 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Severe respiratory failure | 5 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Severe cardiac failure | 3 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Any severe organ failure | 5 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Any severe organ failure | 5 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Severe respiratory failure | 4 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Severe cardiac failure | 1 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Incidence, Severity, and Duration of Organ Failure | Severe renal failure | 1 Participants |
Secondary
Length of Stay in the Hospital
Number of days in the hospital during the first 30 Days of the Study from the SFISD (start of first infusion of study drug) while still alive, for any reason. Includes ICU stay and readmissions. The number of days in the hospital before the patient's death was used in the analysis.(Note: there was only 1 patient death in this study, in the 1.0 mg/kg Auxora group)
Time frame: from admission date into the hospital until discharge date from the hospital
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Length of Stay in the Hospital | 5.9 days | Standard Deviation 3.77 |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Length of Stay in the Hospital | 5.9 days | Standard Deviation 4.46 |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Length of Stay in the Hospital | 7.6 days | Standard Deviation 6.54 |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Length of Stay in the Hospital | 7.1 days | Standard Deviation 5.87 |
Secondary
Mortality by Day 30
Mortality was assessed from randomization through Day 30
Time frame: from randomization and through day 30
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Mortality by Day 30 | 0 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Mortality by Day 30 | 1 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Mortality by Day 30 | 0 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Mortality by Day 30 | 0 Participants |
Secondary
Percentage of Patients With New Onset Severe Respiratory Failure, With gMCP Modeling Analysis for Dose-response Relationship
Analysis of patients without respiratory failure at the time of randomization (defined as a P/F ratio ≤300 measured by an arterial blood gas or imputed from pulse oximetry) who later developed severe respiratory failure during the course of the study.
Time frame: from enrollment and through day 30
Population: Only the subset of patients without respiratory failure at the time of randomization (defined as a P/F ratio ≤300 measured by an arterial blood gas or imputed from pulse oximetry) were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Percentage of Patients With New Onset Severe Respiratory Failure, With gMCP Modeling Analysis for Dose-response Relationship | 0 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Percentage of Patients With New Onset Severe Respiratory Failure, With gMCP Modeling Analysis for Dose-response Relationship | 0 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Percentage of Patients With New Onset Severe Respiratory Failure, With gMCP Modeling Analysis for Dose-response Relationship | 4 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Percentage of Patients With New Onset Severe Respiratory Failure, With gMCP Modeling Analysis for Dose-response Relationship | 4 Participants |
Comparison: Analysis to determine whether a dose-response relationship exists. Multiple possible models (Emax and sigEmax) were tested using gMCP-Mod (Generalized Multiple Comparisons \& Modeling) analysis, performed in 3 steps as described in the SAP: 1) Odds ratio between each dose using logistic regression, with treatment, sex, and risk for organ failure (high/low HCT) as covariates 2) Multiple contrast test 3) Find best-fit dose-response model. Emax model analysis is shown here.p-value: 0.2379Mixed Models Analysis
Comparison: Analysis to determine whether a dose-response relationship exists. Multiple possible models (Emax and sigEmax) were tested using gMCP-Mod (Generalized Multiple Comparisons \& Modeling) analysis, performed in 3 steps as described in the SAP: 1) Odds ratio between each dose using logistic regression, with treatment, sex, and risk for organ failure (high/low HCT) as covariates 2) Multiple contrast test 3) Find best-fit dose-response model. Emax model analysis is shown here.p-value: 0.2379Mixed Models Analysis
Comparison: Analysis to determine whether a dose-response relationship exists. Multiple possible models (Emax and sigEmax) were tested using gMCP-Mod (Generalized Multiple Comparisons \& Modeling) analysis, performed in 3 steps as described in the SAP: 1) Odds ratio between each dose using logistic regression, with treatment, sex, and risk for organ failure (high/low HCT) as covariates 2) Multiple contrast test 3) Find best-fit dose-response model. Emax model analysis is shown here.p-value: 0.2379Mixed Models Analysis
Comparison: Analysis to determine whether a dose-response relationship exists. Multiple possible models (Emax and sigEmax) were tested using gMCP-Mod (Generalized Multiple Comparisons \& Modeling) analysis, performed in 3 steps as described in the SAP: 1) Odds ratio between each dose using logistic regression, with treatment, sex, and risk for organ failure (high/low HCT) as covariates 2) Multiple contrast test 3) Find best-fit dose-response model. Emax model analysis is shown here.p-value: 0.2379Mixed Models Analysis
Comparison: Analysis to determine whether a dose-response relationship exists. Multiple possible models (Emax and sigEmax) were tested using gMCP-Mod (Generalized Multiple Comparisons \& Modeling) analysis, performed in 3 steps as described in the SAP: 1) Odds ratio between each dose using logistic regression, with treatment, sex, and risk for organ failure (high/low HCT) as covariates 2) Multiple contrast test 3) Find best-fit dose-response model. SigEmax model analysis is shown here.p-value: 0.0291Mixed Models Analysis
Comparison: Analysis to determine whether a dose-response relationship exists. Multiple possible models (Emax and sigEmax) were tested using gMCP-Mod (Generalized Multiple Comparisons \& Modeling) analysis, performed in 3 steps as described in the SAP: 1) Odds ratio between each dose using logistic regression, with treatment, sex, and risk for organ failure (high/low HCT) as covariates 2) Multiple contrast test 3) Find best-fit dose-response model. SigEmax model analysis is shown here.p-value: 0.0291Mixed Models Analysis
Comparison: Analysis to determine whether a dose-response relationship exists. Multiple possible models (Emax and sigEmax) were tested using gMCP-Mod (Generalized Multiple Comparisons \& Modeling) analysis, performed in 3 steps as described in the SAP: 1) Odds ratio between each dose using logistic regression, with treatment, sex, and risk for organ failure (high/low HCT) as covariates 2) Multiple contrast test 3) Find best-fit dose-response model. SigEmax model analysis is shown here.p-value: 0.0291Mixed Models Analysis
Comparison: Analysis to determine whether a dose-response relationship exists. Multiple possible models (Emax and sigEmax) were tested using gMCP-Mod (Generalized Multiple Comparisons \& Modeling) analysis, performed in 3 steps as described in the SAP: 1) Odds ratio between each dose using logistic regression, with treatment, sex, and risk for organ failure (high/low HCT) as covariates 2) Multiple contrast test 3) Find best-fit dose-response model. Emax model analysis is shown here.p-value: 0.0291Mixed Models Analysis
Secondary
Re-hospitalization for Acute Pancreatitis by Day 30
The proportion of patients who were re-hospitalized for either acute pancreatitis, or the development of pancreatic necrosis/necrotizing pancreatitis through the Day 30 visit.
Time frame: time from initial date of hospital discharge through date of re-hospitalization through day 30
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | All rehospitalizations due to AP | 4 Participants |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - alcohol | 2 Participants |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - biliary | 1 Participants |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - hypertriglyceridemia | 0 Participants |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - abdominal pain (from AP) | 1 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - hypertriglyceridemia | 1 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - biliary | 0 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - abdominal pain (from AP) | 0 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | All rehospitalizations due to AP | 3 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - alcohol | 2 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - abdominal pain (from AP) | 0 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - alcohol | 0 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | All rehospitalizations due to AP | 1 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - hypertriglyceridemia | 0 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - biliary | 1 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | All rehospitalizations due to AP | 0 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - biliary | 0 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - abdominal pain (from AP) | 0 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - hypertriglyceridemia | 0 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Re-hospitalization for Acute Pancreatitis by Day 30 | Cause of AP rehospitalization - alcohol | 0 Participants |
Secondary
Solid Food Tolerance
Number (and percentage) of patients who tolerated solid food at 48hrs, 72hrs, and 96hrs from start of first infusion of study drug, as well as at time of first discharge from hospital
Time frame: from SFISD to 48 hours, 72 hours and 96 hours and at time of hospital discharge (up to 30 days after SFISD)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Solid Food Tolerance | 48hrs | 23 Participants |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Solid Food Tolerance | 72hrs | 27 Participants |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Solid Food Tolerance | 96hrs | 37 Participants |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Solid Food Tolerance | Hospital Discharge | 44 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Solid Food Tolerance | 72hrs | 30 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Solid Food Tolerance | 96hrs | 35 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Solid Food Tolerance | Hospital Discharge | 41 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Solid Food Tolerance | 48hrs | 26 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Solid Food Tolerance | 96hrs | 31 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Solid Food Tolerance | 72hrs | 25 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Solid Food Tolerance | Hospital Discharge | 39 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Solid Food Tolerance | 48hrs | 23 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Solid Food Tolerance | Hospital Discharge | 42 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Solid Food Tolerance | 72hrs | 30 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Solid Food Tolerance | 48hrs | 21 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Solid Food Tolerance | 96hrs | 30 Participants |
Secondary
The Persistence of SIRS ≥48 Hours After the SFISD
The proportion of patients who developed persistence of SIRS ≥48 Hours after the SFISD analyzed through Day 30. If the patient was discharged before 48 Hours after the SFISD, the last available post-treatment data was used to define the SIRS status at 48 hours after the SFISD based on the LOCF method.
Time frame: from SFISD through day 30
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | The Persistence of SIRS ≥48 Hours After the SFISD | 11 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | The Persistence of SIRS ≥48 Hours After the SFISD | 8 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | The Persistence of SIRS ≥48 Hours After the SFISD | 15 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | The Persistence of SIRS ≥48 Hours After the SFISD | 13 Participants |
Secondary
Time to Medically Indicated Discharge
The time (in hours) to medically indicated discharge, defined as the number of days from the SFISD to the first date of meeting the criteria below: * the patient tolerated solid food, as defined by the main analytical approach; and * abdominal pain was controlled or resolved, which was defined by a reduction in pain, as assessed by the PNRS scale, of ≥50% from the peak level in the first 24 hours and no use of opioids; and * no clinical evidence of an infection requiring continued hospitalization. Kaplan-Meier (K-M) estimates of median time to medically indicated discharge are shown.
Time frame: from start of first infusion of study drug through time of hospital discharge or through Day 30, whichever occurs first
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Time to Medically Indicated Discharge | 89 hours |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Time to Medically Indicated Discharge | 104.5 hours |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Time to Medically Indicated Discharge | 109.5 hours |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Time to Medically Indicated Discharge | 104 hours |
Other Pre-specified
Change in ANC/ALC Ratio and IL-6 Levels
Exploratory analysis of serum biomarkers.
Time frame: from randomization through day 30
Other Pre-specified
Change in Urine NGAL
Exploratory analysis of urine biomarker NGAL
Time frame: from randomization through day 30
Other Pre-specified
Development of Infected Pancreatic Necrosis
Exploratory. Percentage of Patients with Infected Pancreatic Necrosis at Day 30 after SFISD.
Time frame: from end of first infusion of study drug through Day 30 CECT
Population: Count and percentage is based on the number of subjects with non-missing Screening and Day 30 Visit (or post-treatment unscheduled visit) CTCE reading results.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Development of Infected Pancreatic Necrosis | 1 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Development of Infected Pancreatic Necrosis | 0 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Development of Infected Pancreatic Necrosis | 0 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Development of Infected Pancreatic Necrosis | 1 Participants |
Other Pre-specified
Development of Sepsis
Exploratory. Count of patients who experienced sepsis after SFISD.
Time frame: from end of first infusion of study drug through day 30
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Development of Sepsis | 0 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Development of Sepsis | 2 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Development of Sepsis | 3 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Development of Sepsis | 1 Participants |
Other Pre-specified
Number of Patients That Developed Any New Onset Necrotizing Pancreatitis by Day 30
The number of patients who had no necrotizing pancreatitis at screening, and developed any amount of necrotizing pancreatitis based on the Day 30 visit CECT reading results.
Time frame: From SFISD to Day 30
Population: Analysis includes only patients who had a CECT at screening that showed no necrotizing pancreatitis, and who also had a non-missing Day 30 visit (or post-treatment unscheduled visit) CECT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Number of Patients That Developed Any New Onset Necrotizing Pancreatitis by Day 30 | 11 Participants |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Number of Patients That Developed Any New Onset Necrotizing Pancreatitis by Day 30 | 27 Participants |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Number of Patients That Developed Any New Onset Necrotizing Pancreatitis by Day 30 | 24 Participants |
| Placebo (1.25, 0.625, or 0.3125 mL/kg) | Number of Patients That Developed Any New Onset Necrotizing Pancreatitis by Day 30 | 17 Participants |
Other Pre-specified
Win Ratio for Auxora vs. Placebo
The win ratio compares effectiveness of each Auxora dose group with the placebo group. It is calculated by dividing the total number of wins by the total number of losses, with a win ratio \>1 indicating better outcomes for Auxora treatment. Comparison between placebo and Auxora outcomes was performed in a hierarchical manner, in the following order: 1. Mortality (see Outcome Measure 11), 2. New Onset Severe Respiratory Failure (see Outcome Measure 2), 3. New Onset Necrotizing Pancreatitis at Day 30 (see Outcome Measure 18), and 4. Time to Medically Indicated Discharge (see Outcome Measure 5). Stratification was performed by sex (male or female) and then by HCT (higher or lower). Subjects with respiratory failure at baseline were imputed as a non-event. Subjects with missing necrotizing pancreatitis evaluation or positive necrotizing pancreatitis at screening were imputed as a non-event. Subjects missing a necrotizing pancreatitis evaluation at Day 30 were imputed as a non-event.
Time frame: from randomization through Day 30
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Auxora 2.0 mg/kg (1.25 mL/kg) | Win Ratio for Auxora vs. Placebo | Stratified Win Ratio - ALL | 1.640 Win Ratio |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Win Ratio for Auxora vs. Placebo | Stratified Win Ratio - Balthazar D or E | 2.071 Win Ratio |
| Auxora 2.0 mg/kg (1.25 mL/kg) | Win Ratio for Auxora vs. Placebo | Stratified Win Ratio - High HCT | 1.507 Win Ratio |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Win Ratio for Auxora vs. Placebo | Stratified Win Ratio - ALL | 1.177 Win Ratio |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Win Ratio for Auxora vs. Placebo | Stratified Win Ratio - High HCT | 1.241 Win Ratio |
| Auxora 1.0 mg/kg (0.625 mL/kg) | Win Ratio for Auxora vs. Placebo | Stratified Win Ratio - Balthazar D or E | 1.501 Win Ratio |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Win Ratio for Auxora vs. Placebo | Stratified Win Ratio - ALL | 1.123 Win Ratio |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Win Ratio for Auxora vs. Placebo | Stratified Win Ratio - Balthazar D or E | 1.613 Win Ratio |
| Auxora 0.5 mg/kg (0.3125 mL/kg) | Win Ratio for Auxora vs. Placebo | Stratified Win Ratio - High HCT | 1.200 Win Ratio |
p-value: 0.0372Finkelstein-Schoenfeld
p-value: 0.4918Finkelstein-Schoenfeld
p-value: 0.6224Finkelstein-Schoenfeld