- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02692391
A Randomized Controlled Pilot Trial of Indomethacin in Acute Pancreatitis
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
-
-
Pennsylvania
-
Pittsburgh, Pennsylvania, United States, 15213
- Univeristy of Pittsburgh
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Placebo
6 doses, Q8hrs for a total period of 48 hours
|
Glycerin placebo suppositories which are identical in shape, size, color, and packaging to rectal indomethacin
Other Names:
|
Active Comparator: Indomethacin suppository
Loading dose :100mg Maintenance dose: 50 mg, Q8hrs for a total period of 48 hours (5 doses)
|
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.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Systemic Inflammatory Response Syndrome (SIRS) Score
Time Frame: The change in the SIRS score (48 hours - baseline)
|
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.
Time Frame: 48 hours
|
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
Time Frame: 7 days
|
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
Time Frame: 1 month
|
Enrolled subjects that died.
A death indicates a worse outcome.
|
1 month
|
Collaborators and Investigators
Sponsor
Investigators
- Study Chair: Georgios I Papachristou, MD PhD, Ohio State University
Publications and helpful links
General Publications
- Sotoudehmanesh R, Eloubeidi MA, Asgari AA, Farsinejad M, Khatibian M. A randomized trial of rectal indomethacin and sublingual nitrates to prevent post-ERCP pancreatitis. Am J Gastroenterol. 2014 Jun;109(6):903-9. doi: 10.1038/ajg.2014.9. Epub 2014 Feb 11.
- Freeman ML, Guda NM. Prevention of post-ERCP pancreatitis: a comprehensive review. Gastrointest Endosc. 2004 Jun;59(7):845-64. doi: 10.1016/s0016-5107(04)00353-0. No abstract available.
- Machicado JD, Mounzer R, Paragomi P, Pothoulakis I, Hart PA, Conwell DL, de-Madaria E, Greer P, Yadav D, Whitcomb DC, Lee PJ, Hinton A, Papachristou GI. Rectal Indomethacin Does Not Mitigate the Systemic Inflammatory Response Syndrome in Acute Pancreatitis: A Randomized Trial. Clin Transl Gastroenterol. 2021 Oct 27;12(11):e00415. doi: 10.14309/ctg.0000000000000415.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Pancreatic Diseases
- Pancreatitis
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Peripheral Nervous System Agents
- Enzyme Inhibitors
- Analgesics
- Sensory System Agents
- Anti-Inflammatory Agents, Non-Steroidal
- Analgesics, Non-Narcotic
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Cyclooxygenase Inhibitors
- Reproductive Control Agents
- Gout Suppressants
- Tocolytic Agents
- Indomethacin
Other Study ID Numbers
- STUDY19050212
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Acute Pancreatitis
-
Centre Hospitalier Universitaire de NiceRecruiting
-
John Gasdal KarstensenCompleted
-
Tianjin Nankai HospitalCompletedAcute PancreatitisChina
-
Mayo ClinicNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)CompletedAcute Pancreatitis (AP) | Gallstone Pancreatitis | Alcoholic Pancreatitis | Trauma Acute Pancreatitis | Hypertriglyceridemia Acute Pancreatitis | Idiopathic (Unknown) Acute Pancreatitis | Medication Induced Acute Pancreatitis | Cancer Acute Pancreatitis | Miscellaneous (i.e. Acute on Chronic Pancreatitis)United States
-
Northern State Medical UniversityCompleted
-
Erzhen ChenRenJi HospitalUnknownPancreatitis,Acute NecrotizingChina
-
Orlando Health, Inc.Mayo Clinic; University of Alabama at Birmingham; University of Southern California and other collaboratorsActive, not recruitingPancreatitis,Acute NecrotizingUnited States
-
University of OuluCopenhagen University Hospital, HvidovreUnknownAcute Necrotizing PancreatitisFinland
-
Sichuan Academy of Medical SciencesPeking Union Medical College HospitalCompleted
-
Interscope, Inc.CompletedAcute Pancreatitis | Necrotizing Pancreatitis | Acute Pancreatic NecrosisUnited States, Netherlands, Germany
Clinical Trials on Placebo
-
SamA Pharmaceutical Co., LtdUnknownAcute Bronchitis | Acute Upper Respiratory Tract InfectionKorea, Republic of
-
National Institute on Drug Abuse (NIDA)CompletedCannabis UseUnited States
-
AstraZenecaParexel; Spandauer Damm 130; 14050; Berlin, GermanyCompletedMale Subjects With Type II Diabetes (T2DM)Germany
-
Heptares Therapeutics LimitedCompletedPharmacokinetics | Safety IssuesUnited Kingdom
-
GlaxoSmithKlineCompletedPulmonary Disease, Chronic ObstructiveUnited Kingdom, Netherlands
-
ItalfarmacoCompletedBecker Muscular DystrophyNetherlands, Italy
-
Shijiazhuang Yiling Pharmaceutical Co. LtdXuanwu Hospital, BeijingCompleted
-
GlaxoSmithKlineCompletedInfections, BacterialUnited States
-
West Penn Allegheny Health SystemCompletedAsthma | Allergic RhinitisUnited States