CM4620 Injectable Emulsion Versus Supportive Care in Patients With Acute Pancreatitis and SIRS

Study Overview
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Brief Summary
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This open-label, dose-response study will evaluate the safety and efficacy of CM4620-IE in patients with acute pancreatitis and accompanying SIRS. The study will consist of two phases. The first phase will consist of 4 female and 4 male patients (cohorts 1 and 2, respectively), enrolled concurrently, randomized in a 3:1 ratio to receive CM4620-IE plus standard of care versus standard of care alone. Planned doses for first phase will be CM4620-IE 1.0 mg/kg on Day 1 and then 1.4 mg/kg on Days 2 - 4. The second phase will consist of 8 female and 8 male patients (cohorts 3 and 4, respectively), enrolled concurrently, randomized in a 3:1 ratio to receive CM4620-IE plus standard of care versus standard of care alone. Planned doses for second phase will be CM4620-IE 2.08 mg/kg on Days 1 and 2 and then 1.6 mg/kg on Days 3 and 4. Dose escalation to second phase would only occur if needed for efficacy reasons and if no events suggesting a safety signal would occur with higher dosing. The study is not powered for the analysis of study data with inferential statisitcs as the primary purpose of the study is to explore what endpoints would be most appropriate for future trials.

Detailed Description
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After review of the efficacy, tolerability and safety data from cohorts 1 and 2 by the sponsor and the United States Food and Drug Administration, the decision was made to continue the low-dose regimen (CM4620-IE 1.0 mg/kg on Day 1 and then 1.4 mg/kg on Days 2 - 4) in cohort 3. Cohort 4 received the high-dose regimen (CM4620-IE 2.08 mg/kg on Days 1 and 2 and then 1.6 mg/kg on Days 3 and 4) as planned. Efficacy analysis were combined because no dose escalation occurred in cohort 3. Patients were followed for 90 days after randomization.

Official Title
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An Open-Label, Dose-Response Study of CM4620 Injectable Emulsion (CM4620-IE) in Patients With Acute Pancreatitis and Accompanying Systemic Inflammatory Response Syndrome (SIRS)

Conditions
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Acute Pancreatitis, Systemic Inflammatory Response Syndrome

Intervention / Treatment
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* Drug: CM4620 Injectable Emulsion (Low Dose)
* Drug: CM4620 Injectable Emulsion (High Dose)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of acute pancreatitis established by the presence of abdominal pain consistent with acute pancreatitis and 1 of the following 2 criteria: Serum lipase and/or serum amylase > 3 times the upper limit of normal (ULN); Characteristic findings of acute pancreatitis on abdominal imaging; A SpO2 <96% with a FiO2 of 21% (room air) to 27%, or a SpO2 <97% with a FiO2 ≥28%; Diagnosis of SIRS, defined by the presence of at least 2 of the following 4 criteria: Temperature < 36°C or > 38°C; Heart rate > 90 beats/minute; Respiratory rate >20 breaths/minute or arterial carbon dioxide tension (PaCO2) <32 mmHg; White blood cell count (WBC) >12,000 mm3, or <4,000 mm3, or > 10% immature (band) forms; No evidence of pancreatic necrosis on contrast-enhanced computed tomography (CECT performed in the 18 hours prior to consent or after consent and before Day 1; Adults ≥ 18 years of age; A female patient of child bearing potential who is sexually active with a male partner must be willing to practice acceptable methods of birth control for 365 days after the last dose of CM4620-IE; A male patient who is sexually active with a female partner of childbearing potential must be willing to practice acceptable methods of birth control for 365 days after the last dose of CM4620-IE and must not donate sperm for 365 days. Willing and able to, or have a legal authorized representative (LAR) that is willing and able to, provide informed consent to participate, and to cooperate with all aspects of the protocol. Exclusion Criteria: Any concurrent clinical condition that a study physician believes could potentially pose an unacceptable health risk to the patient while involved in the study, including a CV SOFA score of 4 at the time of screening, or may limit expected survival to <6 months; Suspected presence of cholangitis in the judgment of the treating investigator; ERCP performed in the previous 7 days; Any malignancy being treated with chemotherapy or immunotherapy; Any autoimmune disease being treated with immunosuppressive medication or immunotherapy; History of: Acute pancreatitis with pancreatic necrosis on Contrast-Enhanced Computed Tomography (CECT) of the pancreas; Chronic pancreatitis, pancreatic necrosis or necrosectomy, or pancreatic enzyme replacement therapy; Biopsy proven cirrhosis, portal hypertension, hepatic failure/hepatic encephalopathy; Known hepatitis B or C, or HIV; History of organ or hematologic transplant; Resuscitated cardiac arrest, myocardial infarction, revascularization, cardiovascular accident (CVA) in the 30 days prior to Day 1; Current renal replacement therapy; Current known abuse of cocaine or methamphetamine; Known to be pregnant or are nursing; Participated in another study of an investigational drug or therapeutic medical device in the 30 days prior to Day 1; History of allergy to eggs or known hypersensitivity to any components of CM4620-IE.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose Group<br>Phase 1: Cohorts 1 & 2 will consist of 4 female and 4 male patients enrolled concurrently who will be randomized 3:1 to receive CM4620-IE plus standard of care versus standard of care alone. Planned doses for patients who are randomized to receive CM4620-IE are 1.0 mg/kg on Days 1 and 1.4 mg/kg on Days 2-4. | Drug: CM4620 Injectable Emulsion (Low Dose)<br>* CM4620-IE 1.0 mg/kg on Day 1 and then 1.4 mg/kg on Days 2-4, during the first phase of the study (Cohorts 1 and 2). All doses of CM4620-IE will be administered intravenously (IV) over 4 hours.<br>* Other names: CM4620-IE (Low Dose);|
| Experimental: High Dose Group<br>Phase 2: Cohorts 3 & 4 will consist of 8 female and 8 male patients enrolled concurrently who will be randomized 3:1 to receive CM4620-IE plus standard of care versus standard of care alone. Planned doses for patients who are randomized to receive CM4620-IE are 2.08 mg/kg of CM4620-IE on Days 1 and 2, and 1.6 mg/kg on Days 3 and 4. | Drug: CM4620 Injectable Emulsion (High Dose)<br>* CM4620-IE 2.08 mg/kg on Days 1 and 2 and then 1.6 mg/kg on Days 3 and 4, during the second phase of the study (Cohorts 3 and 4). All doses of CM4620-IE will be administered intravenously (IV) over 4 hours.<br>* Other names: CM4620-IE (High Dose);|
| No Intervention: Standard of Care<br>For all cohorts, patients will be randomized 3:1 to CM4620-IE plus standard of care versus standard of care alone. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Safety and Tolerability of CM4620-IE in Patients With Acute Pancreatitis and Accompanying Systemic Inflammatory Response Syndrome (SIRS) or Hypoxemia. | Safety and tolerability will be assessed by monitoring the frequency, duration and severity of treatment-emergent adverse events (TEAEs) throughout the study period. | 90 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Patients With a Change in Computed Tomography Severity Index (CTSI) Score Between Screening and Day 5 (or Discharge, if Earlier) | CTSI score measures abnormal pancreatic morphology and is the sum of two subscales. The Balthazar subscale rates pancreatic CT image findings on a scale of 0 (normal) to 4 (2 or more peri-pancreatic fluid collections. The Pancreatic Necrosis subscale rates pancreatic necrosis from 0 (none) to 6 (>50%). The two subscales are summed for a CTSI score of 0-3 (mild AP), 4-6 (moderate AP), and 7-10 (severe AP). | 5 days (or discharge, if earlier) | 
| The Number of Patients Tolerating Solid Food | Defined as eating ≥ 50% of a solid meal without vomiting or an increase in pain | at 72 hours (or discharge, if earlier) | 
| The Number of Patients Tolerating Solid Food | Defined as eating ≥ 50% of a solid meal without vomiting or an increase in pain | at Day 10 (or discharge, if earlier) | 
| Percentage of Patients With Persistent Systemic Inflammatory Response Syndrome (SIRS) | The presence of SIRS was defined as the presence of at least 2 of the following 4 criteria: Temperature < 36°C or > 38°C; Heart rate > 90 beats/minute; Respiratory rate > 20 breaths/minute or arterial carbon dioxide tension (PaCO2) < 32 mmHg; White blood cell count (WBC) > 12,000 cells/mm3 or < 4,000 cells/mm3 or > 10% immature (band) forms. The SIRS score was determined at Screening, prior to randomization, and every 12 hours until Day 6, after which it was determined every 24 hours. | ≥ 48 hours | 
| IL-6 Values in Patients With a Maximum IL-6 Value ≥ 150 pg/mL in the First 24 Hours | Assess blood serum samples to be analyzed for interleuken (IL-6) llevels pg/mL collected in the first 24 hours and daily thereafter. Samples were sent to the central laboratory. The results were not provided to the Principal Investigator or treating physician. | Day 10 (or discharge, if earlier) | 
| Median Days in Hospital | Length of stay in hospital in days (randomization to discharge) | discharge |