A Randomized Controlled Pilot Trial of Indomethacin in Acute Pancreatitis

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled pilot trial seeking to evaluate the efficacy of rectal indomethacin in abrogating systemic inflammation and subsequently organ failure and mortality in patients with AP and positive SIRS score.

Detailed Description
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Background: AP is an inflammatory disease with a highly variable clinical course that is potentially lethal. This disease is currently the leading cause of gastrointestinal-related hospital admissions in the United States and continues to rise in incidence. The inciting event leading to the development of AP is the premature activation of the digestive pro-enzyme trypsinogen to trypsin within pancreatic acinar cells, resulting in pancreatic auto-digestion and inflammation. Inflammation localized to the gland can subsequently progress to a systemic inflammatory response affecting distant organs. Studies have revealed a key role for phospholipase A2 in propagating this inflammatory response by inducing the production of inflammatory mediators, including arachidonic acid metabolites. Elevated levels of phospholipase A2 have been found in the serum of patients with AP who develop severe complications, including pancreatic necrosis, shock, and OF. The in vitro inhibition of phospholipase A2 using NSAIDs has been evaluated as a potential treatment strategy for AP, with indomethacin shown to be the most potent inhibitor among 17 tested agents. NSAIDs also inhibit the interaction of neutrophils with endothelial cells, thus preventing the accumulation of neutrophils at the site of injury. In animal models of AP, NSAIDs have been shown to attenuate AP severity and improve survival. Most human studies, however, have primarily assessed the role of NSAIDs in PEP prophylaxis. A meta-analysis of 4 randomized, controlled studies evaluating this effect revealed a protective role for these medications, and a recent multicenter, randomized controlled trial found that administrating rectal indomethacin to patients at increased risk for PEP significantly reduced the incidence and severity of pancreatitis. In 1985, a small randomized controlled trial (n=30) of rectal indomethacin in patients with AP reported a significant decrease in the duration of pain. This is the only study to date evaluating NSAIDs following the onset of AP and did not evaluate systemic inflammation. The effect of rectal indomethacin in mitigating disease progression in patients at risk for developing severe disease thus remains to be evaluated. SIRS is a simple clinical score, ranging from 0-4, that utilizes objective, routine clinical parameters (body temperature, heart rate, respiratory rate or arterial carbon dioxide tension and white blood count) that directly reflect the underlying inflammatory response. The persistence of SIRS, defined by the presence of a SIRS score ≥2 at 48 hrs following presentation, has been shown to be significantly associated with the development of OF, pancreatic necrosis and death in patients with AP. Additionally, serum levels of CRP at 48 hours following admission have also been closely correlated with the development of OF. Objective: Our proposed randomized, double-blind, placebo-controlled pilot trial seeks to evaluate the efficacy of rectal indomethacin in abrogating systemic inflammation in patients with acute pancreatitis (AP) and systemic inflammatory response syndrome (SIRS). Specific Aims: Our long-term goal is to alter the clinical course of AP in patients who are at high risk for the development of organ failure (OF) and death. The objective of this randomized, double-blind, placebo-controlled pilot trial is to evaluate the efficacy of rectal indomethacin on attenuating systemic inflammation in patients with AP who also have SIRS. The investigators hypothesize that the treatment of patients with AP and SIRS with therapeutic doses of rectal indomethacin will mitigate the inflammatory response through the inhibition of inflammatory mediators. The investigators will also test the hypothesis by enrolling 42 patients randomized to receive either rectal indomethacin or placebo for 48 hours and pursuing the following specific aims: Aim 1. Evaluate the effect of rectal indomethacin on systemic inflammation as measured by the change in mean SIRS score and serum CRP levels following 48hrs of treatment in patients with AP and SIRS; and Aim 2. Evaluate the impact of rectal indomethacin on the development of OF and mortality. Significance: The proposed study will thus be the first attempt at evaluating the therapeutic role of NSAIDs in patients with AP and SIRS who are at high risk for the development of OF and for whom no effective pharmacological therapy is currently available. Pilot data generated will serve as a platform for a larger scale study that will validate the efficacy of indomethacin in the treatment of AP.

Official Title
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A Randomized Controlled Pilot Trial of Indomethacin in Acute Pancreatitis

Conditions
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Acute Pancreatitis

Intervention / Treatment
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* Drug: Indomethacin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients ages 18 or above admitted to UPMC with a diagnosis of AP based on at least 2 of the following criteria: (i) abdominal pain characteristic of AP (ii) serum amylase and/or lipase ≥ 3 times the upper limit of normal (iii) characteristic findings of AP on abdominal CT scan will be screened for study enrollment. Patients with SIRS (≥ 2 of the following criteria: temperature <36°C or >38°C, heart rate >90/min, respiratory rate >20/min OR PaCO2<32 mmHg, WBC <4,000/mm3, >12,000/mm3 or >10% bands) upon hospital admission or who develop SIRS during their first week of hospitalization Exclusion Criteria: Presence of OF (shock defined by SBP<90mmHg, PO2<60mmHg on room air or need for mechanical ventilation, Cr≥2mg/dL) Presence of renal dysfunction (Cr>1.5mg/dL) Active peptic ulcer disease Pregnancy Use of daily NSAIDs within 1 week of presentation Allergy to NSAIDs.

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>6 doses, Q8hrs for a total period of 48 hours | Drug: Placebo<br>* Glycerin placebo suppositories which are identical in shape, size, color, and packaging to rectal indomethacin<br>* Other names: Glycerin;|
| Active Comparator: Indomethacin suppository<br>Loading dose :100mg Maintenance dose: 50 mg, Q8hrs for a total period of 48 hours (5 doses) | Drug: Indomethacin<br>* Rectal indomethacin will be administered as 100 mg loading doses following by 5 maintenance doses of 50 mg at internals of 8 hours for total of 48 hours.<br>* Other names: Indocin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systemic Inflammatory Response Syndrome (SIRS) Score | SIRS is a simple clinical score, ranging from 0-4, that utilizes objective, routine clinical parameters (body temperature, heart rate, respiratory rate or arterial carbon dioxide tension and white blood count) that directly reflect the underlying inflammatory response. A lower change in SIRS score (negative number) indicates a better outcome (less inflammation). | The change in the SIRS score (48 hours - baseline) | 
| C-Reactive Protein (CRP) Levels. | CRP levels at 48 hours after enrollment minus CRP levels at enrollment (baseline). A negative number indicates a better outcome (less inflammation). | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Development of Organ Failure | Including respiratory, renal and cardiovascular failures defined as modified Marshal score of equal and greater than 2. The minimum and maximum values in the modified Marshal score for each organ failure range from 0 to 4 with a higher value representing worse outcomes. | 7 days | 
| Mortality | Enrolled subjects that died. A death indicates a worse outcome. | 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute pancreatitis, Indomethacin, Organ failure, Prevention