Clinical trial NCT04681066: A Study of Auxora in Patients With Acute Pancreatitis and Accompanying SIRS
Official title: A Randomized, Double-Blind, Placebo Controlled Dose-Ranging Study of Auxora in Patients With Acute Pancreatitis and Accompanying Systemic Inflammatory Response Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Pancreatitis
Systemic Inflammatory Response Syndrome
Lead sponsor: CalciMedica, Inc.
Sponsor class: INDUSTRY
First posted: 2020-12-23
Enrollment: 216
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Time to solid food tolerance
timeFrame: from start of first infusion of study drug (SFISD) to day 30
Secondary outcomes:
measure: Solid food tolerance
timeFrame: from SFISD to 48 hours, 72 hours and 96 hours and at time of hospital discharge
measure: Time to medically indicated discharge
timeFrame: from start of first infusion of study drug and through time of hospital discharge or through Day 30, whichever occurs first
measure: Length of stay in the hospital
timeFrame: from admission date into the hospital until discharge date from the hospital
measure: Length of stay in the ICU for patients admitted to the ICU
timeFrame: from admission into ICU until discharge from ICU
measure: Re-hospitalization for acute pancreatitis by Day 30
timeFrame: time from initial date of hospital discharge through date of re-hospitalization through day 30
measure: Change in severity of acute pancreatitis by CTSI score from screening to Day 30
timeFrame: from informed consent through day 30
measure: Development of pancreatic necrosis ≥30% and >50%
timeFrame: from enrollment CECT through Day 30 CECT
measure: The persistence of SIRS ≥48 hours after the SFISD
timeFrame: from SFISD through day 30
measure: Incidence, severity, and duration of organ failure
timeFrame: from enrollment and through day 30
measure: Mortality by Day 30
timeFrame: from randomization and through day 30
measure: Change in pain score
timeFrame: from enrollment through day 30
measure: Change in opioid use
timeFrame: from enrollment through day 30
Other outcomes:
measure: Development of infected pancreatic necrosis
timeFrame: from enrollment CECT through Day 30 CECT
measure: Development of sepsis
timeFrame: from randomization through day 30
measure: Hospital procedures for the management of pancreatic necrosis
timeFrame: from randomization through day 30
measure: Change in GCSI-DD score
timeFrame: from randomization through day 30
measure: Change in albumin
timeFrame: from randomization through day 30
measure: Change in ANC/ALC ratio and IL-6 levels
timeFrame: from randomization through day 30
measure: Change in urine NGAL
timeFrame: from randomization through day 30
Locations:
city: Long Beach
country: United States
facility: Long Beach Medical Center
state: California
city: Los Angeles
country: United States
facility: LA County Hospital - USC
state: California
city: Los Angeles
country: United States
facility: Cedars Sinai
state: California
city: Orange
country: United States
facility: University of California at Irvine Medical Center
state: California
city: Torrance
country: United States
facility: Harbor UCLA Medical Center
state: California
city: Torrance
country: United States
facility: Torrance Memorial Medical Center
state: California
city: Stamford
country: United States
facility: The Stamford Hospital
state: Connecticut
city: Sarasota
country: United States
facility: Sarasota Memorial Health Care System
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Boise
country: United States
facility: St. Luke's Regional Medical Center
state: Idaho
city: Chicago
country: United States
facility: Northwestern University Hospital
state: Illinois
city: Louisville
country: United States
facility: Robley Rex VA Medical Center
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Saint Louis Park
country: United States
facility: Methodist Hospital
state: Minnesota
city: Saint Paul
country: United States
facility: Regions Hospital
state: Minnesota
city: Columbia
country: United States
facility: University of Missouri School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Manhasset
country: United States
facility: Northshore University Hospital
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Memphis
country: United States
facility: Regional One Health
state: Tennessee
city: Fort Worth
country: United States
facility: John Peter Smith Hospital
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Houston
country: United States
facility: UT Health Houston
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Charleston
country: United States
facility: CAMC Institute for Academic Medicine
state: West Virginia
city: Bīkaner
country: India
facility: SPMC
city: Chandigarh
country: India
facility: PGIMER, Chandigarh
city: Hyderabad
country: India
facility: Malla Reddy Narayana
city: Jodhpur
country: India
facility: MDM Hospital
city: Kochi
country: India
facility: Lisie Hospital
city: Nagpur
country: India
facility: Seven Star Hospital
city: Puducherry
country: India
facility: JIPMER
city: Pune
country: India
facility: MTES' Sanjeevan Hospital
city: Rājkot
country: India
facility: Shree Giriraj Multispeciality Hospital
city: Shimla
country: India
facility: IGMU (India Gandhi Medical)
Study officials:
affiliation: CalciMedica, Inc.
name: Sudarshan Hebbar, MD
role: STUDY_DIRECTOR
References: