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Principal Investigator: Michael William Donnino
Organization: BETH ISRAEL DEACONESS MEDICAL CENTER
Fiscal Year: 2024
Award: $365,165
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
ABSTRACT
There are currently limited medicinal interventions demonstrated to improve outcomes in patients with acute
severe non-autoimmune pancreatitis, a highly morbid and potentially fatal condition which is estimated to afflict
up to 275,000 patients annually in the US.[1] Early-stage mild pancreatitis often self-resolves; however 15-20%
of cases [2] progress to a severe form characterized by a potentially lethal systemic inflammatory response
syndrome with injury to multiple organs and (frequently) respiratory failure. Further clinical deterioration can lead
to necrotizing pancreatitis, which is clinically similar to sepsis and has a reported mortality of up to 30%. [3–6]
Although inflammation is known to be a key driver of disease progression, no anti-inflammatory therapy
investigated to date has shown sufficient efficacy to become part of routine clinical practice. Identification
of a viable medicinal therapy for severe acute pancreatitis thus remains a significant unmet need. In this
application, we propose this need can be met via early delivery of a short course of physiologic-dose
corticosteroids. This commonly used anti-inflammatory therapy has been shown to provide a clear patient
benefit with other diseases which trigger systemic inflammation, multi-organ injury, and respiratory failure (e.g.
sepsis, Acute Respiratory Distress Disorder (ARDS), and most recently COVID-19), but has been poorly studied
in pancreatitis. The few published pilot trials of this therapy for severe acute pancreatitis have shown
corticosteroids shorten the duration of shock and may improve mortality, but these results must be validated in
a series of increasingly large, rigorous clinical trials before this therapy is widely accepted by clinicians. Here we
propose the logical first step Phase II trial: a blinded, randomized clinical trial of an early physiological dose
of hydrocortisone vs. placebo in 86 ICU patients with severe acute pancreatitis. The trial will be conducted
by the nationally recognized critical care research team at the Center for Resuscitation Science. We hypothesize
that corticosteroids will attenuate the inflammatory response from pancreatitis resulting in mitigated disease severity
and organ injury. We secondarily hypothesize there will be a concomitant reduction in mortality, though this hypothesis
will be the focus of a follow-up Phase III trial. After baseline assessments, enrollees will receive either 100 mgs of
hydrocortisone or matching placebo intravenously in a blinded fashion every 8 hours for 72 hours (300 mg/day).
The primary trial outcome will be the change in SOFA disease severity score over 72 hours, and from these data
we will conduct a novel sub-study to determine if corticosteroid efficacy is better in specific subgroups whose
clinical outcomes may be the most uncertain. Secondary outcomes will include progression to ARDS, ventilator-
free days, ICU- and hospital-free days, inflammatory biomarker profiles, biomarkers for pancreatic injury, and
adverse events. Overall, this study will provide an initial assessment of a commonly used, and effective anti-
inflammatory therapy as a treatment for a critical illness which generally lacks medicinal therapeutic options.
Terms: <ARDS><Active Follow-up><Acute><Acute Necrotizing Pancreatitis><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adrenal Cortex Hormones><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Adverse Experience><Adverse event><Aeroseb-HC><Airway failure><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Attenuated><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Biological Markers><Blinded><Blood><Blood Reticuloendothelial System><Blood Serum><COVID-19><CSIF><CSIF-10><CV-19><Case Study><Cessation of life><Cetacort><Circulatory Collapse><Clinic><Clinical><Clinical Trials><Coronavirus Infectious Disease 2019><Cort-Dome><Cortef><Cortenema><Corticoids><Corticosteroids><Cortisol><Cortispray><Cortril><Critical Care><Critical Illness><Critically Ill><Cytokine Synthesis Inhibitory Factor><Da Nang Lung><Data><Death><Dermacort><Deterioration><Disease><Disease Progression><Disorder><Dose><Eldecort><Future><HPGF><Hepatocyte-Stimulating Factor><Hospitals><Hour><Hybridoma Growth Factor><Hydrocortisone><Hydrocortisone Used as a Placebo><Hydrocortisone/Placebo><Hydrocortone><Hyperglycemia><Hypernatremia><Hytone><IFN-beta 2><IFNB2><IL-10><IL-6><IL10><IL10A><IL6 Protein><Infection><Inflammation><Inflammatory><Inflammatory Response><Injury><Interleukin 10 Precursor><Interleukin-10><Interleukin-6><Intervention><Intervention Strategies><Intravenous><Length of Stay><Lipase><MGI-2><Measures><Medical><Medicine><Myeloid Differentiation-Inducing Protein><Number of Days in Hospital><Nutracort><Organ><Organ failure><Outcome><Pancreatic Injury><Pancreatic Trauma><Pancreatic enzyme><Pancreatitis><Patients><Phase><Phase 2 Clinical Trials><Phase II Clinical Trials><Physiologic><Physiological><Placebo Control><Placebos><Plasmacytoma Growth Factor><Prevention><Process><Proctocort><Publishing><Quality of Life Assessment><Randomization trial><Randomized><Regimen><Reporting><Research><Respiratory Failure><Respiratory distress><Resuscitation><Safety><Sample Size><Scheme><Science><Sepsis><Series><Serum><Severity of Illness Index><Severity of illness><Sham Treatment><Shock><Shock Lung><Site><Steroid Compound><Steroids><Stiff lung><Stratification><Subgroup><Systemic Inflammatory Response Syndrome><Testing><Therapeutic><Therapy trial><Triacylglycerol Hydrolase><Triacylglycerol Lipase><Triacylglycerol acylhydrolase><Tributyrinase><Triglyceridase><Triglyceride Lipase><Triolean Hydrolase><Trypsinogen><United States><Validation><Ventilator><active followup><acute pancreatitis><adverse consequence><adverse outcome><attenuate><attenuates><bio-markers><biologic marker><biomarker><blood infection><bloodstream infection><case report><circulatory shock><clinical practice><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cytokine><disease severity><early clinical trial><early phase clinical trial><effective therapy><effective treatment><follow up><follow-up><followed up><followup><hospital days><hospital length of stay><hospital stay><hyperglycemic><improved><improved outcome><injuries><injury to organs><innovate><innovation><innovative><interferon beta 2><interventional strategy><mortality><multiorgan injury><novel><organ injury><pancreas enzyme><pancreatitis necrotizing><phase 2 trial><phase 3 trial><phase II protocol><phase II trial><phase III trial><pilot trial><placebo controlled><placebo group><primary outcome><randomisation><randomization><randomized trial><randomized, clinical trials><randomly assigned><response><safety assessment><secondary outcome><sham group><sham therapy><shocks><side effect><systemic inflammation><systemic inflammatory response><tributyrase><validations><wet lung>