Clinical trial NCT02692391
Conditions: Acute Pancreatitis
Keywords: Acute pancreatitis Indomethacin Organ failure Prevention
Sponsor: University of Pittsburgh
Start date: 2013-07-01; Completion date: 2019-12-30
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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:
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.

Arms: arm 1: 6 doses, Q8hrs for a total period of 48 hours arm 2: Loading dose :100mg Maintenance dose: 50 mg, Q8hrs for a total period of 48 hours (5 doses)
Interventions: intervention 1: Indomethacin intervention 2: Placebo
Intervention descriptions: intervention 1: 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. intervention 2: Glycerin placebo suppositories which are identical in shape, size, color, and packaging to rectal indomethacin

Protocol documents:
Prot_000.pdf: 
Page 1 of 4 
 
Study Protocol  
 
 
 
 
 
 
Official Title: A Randomized Controlled Pilot Trial of Indomethacin 
in Acute Pancreatitis 
 
 
 
ClinicalTrials.gov ID (NCT number): NCT02692391    
 
 
 
 
Protocol Date: June 1st, 2013 
 
 
 
 


Page 2 of 4 
 
Scientific 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. 
 
Study Objectives 
 
The predefined primary endpoint was the change in the SIRS score from randomization to 48h 
after the initial intervention, and to compare whether this change was different between subjects 
receiving rectal indomethacin and placebo. Secondary endpoints included (i) change in CRP 
levels from baseline to 48 hours, (ii) change in SIRS score at 24 and 72 hours, (iii) development 
of organ failure, (iv) AP severity, (v) length of hospital stay, and (vi) mortality. Other study 
outcomes included length of ICU stay, and PASS score at 24h, 48h, and 72h.  


Page 3 of 4 
 
 
Study Design & Methods 
 
This was a single-center, parallel-group, double-blind, randomized placebo-controlled trial 
conducted at the University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA. 
 
Randomization and masking 
Patients were randomly assigned in a 1:1 allocation ratio to either rectal indomethacin or placebo 
control within 72 hours of presentation to the emergency department. Simple non-block 
randomization was used. The randomization sequence was generated using computer-based 
random numbers and was only available to the central UPMC pharmacy to ensure allocation 
concealment. A 24-hour pharmacist was assigned to implement the randomization sequence, 
immediately after the study coordinator communicated the enrollment of a participant. Study 
participants, investigators, study coordinators, outcome evaluators, and care providers, were 
blinded to treatment assignment.  
 
Study interventions 
Patients randomized to the intervention arm received a loading dose of two 50-mg indomethacin 
suppositories, which was administered by the registered nurse assigned to the patient’s care 
team. This was followed by five maintenance doses of 50-mg rectally administered at intervals 
of 8 hours for a total of 48 hours and up to six doses. The rectal route was used based on 
previous data demonstrating more rapid and complete availability of the drug as compared to 
oral administration.(3) Patients in the placebo arm received at similar intervals glycerin 
suppositories identical in shape, size, color, and packaging to the indomethacin group. All 
patients were co-administered a daily dose of intravenous 40-mg pantoprazole for 
gastrointestinal prophylaxis. Otherwise, all patients received conventional management 
according to standards of care of AP in the United States.(4, 5)  
 
Data Collection 
Data on demographics, comorbidities, etiology, history of AP, and transfer status, were recorded 
at the time of randomization. SIRS score (0-4) was calculated upon randomization and at 24h, 
48h, and 72h from the time of initial intervention. The levels of C-reactive protein (CRP) were 
measured at the time of randomization and at 48h from the initial intervention. Other clinical 
outcomes and treatment strategies were evaluated daily until the end of the hospitalization. The 
development of organ failure (OF) was defined as a score ≥ 2 for cardiovascular, respiratory or 
renal systems, using the Modified Marshall Scoring System.(6) Duration of organ failure for 
over 48h was defined as persistent OF. Severity of AP during the hospital admission was 
categorized as mild, moderately-severe, and severe based on the Revised Atlanta 
Classification.(7) Daily recorded data was used for post-hoc calculation of the pancreatitis 
activity scoring system (PASS) at baseline and daily post-intervention.(8) This score is the 
summation of the following five parameters: organ failure (×100 per organ), oral intolerance 
(×40), systemic inflammatory response syndrome (SIRS) (×25 per criterion), morphine 
equivalent dose (MED) (×5), and pain score (×5). Detailed information on fluid resuscitation 
within the first 24h was obtained from medical records. Abdominal computed tomography (CT) 
was obtained at the discretion of the care providers, and was interpreted by expert abdominal 
radiologists, who were blinded to the study arm. If more than one CT scan was performed during 


Page 4 of 4 
 
the admission, the one obtained closest to the third day of presentation was used to report the 
presence of pancreatic and peripancreatic necrosis.    
 
The development of adverse events (AEs) was monitored by the study coordinator on a daily 
basis during the hospitalization. Any major AEs were reported to the IRB and DSMB. These 
reportable AEs included gastrointestinal bleeding, perforated viscus, acute kidney injury 
(increase in serum creatinine ≥0.3 mg/dL within 48 hours), allergic reaction, myocardial 
infarction, and death. 
 
Eligibility Criteria  
 
Adult subjects (≥18 years of age) admitted to UPMC with a diagnosis of AP were assessed for 
eligibility. Acute pancreatitis was defined based on at least two of the following criteria: 
abdominal pain characteristic of AP; serum amylase and/or lipase greater than 3 times the upper 
limit of normal; or characteristic findings of AP on cross sectional images.(1) Patients with SIRS 
within the first 72 hours (h) of initial hospital presentation were eligible for randomization. SIRS 
was defined by the presence of two or more of the following criteria: a) pulse >90 beats/min; b) 
respiratory rate >20/min or PaCO2 <32 mmHg; c) temperature >38°C or <36°C; and d) white 
blood cell count >12,000 or <4000 cells/mm3 or >10% immature neutrophils (bands).(2) 
Exclusion criteria included SIRS onset after 72h of initial hospital presentation, cardiovascular 
failure (systolic blood pressure ≤ 90 mmHg), respiratory failure (partial pressure of oxygen < 60 
mmHg), renal failure (creatinine > 1.5 mg/dL), active peptic ulcer disease, pregnancy, active use 
of NSAIDs within 1 week of presentation, and allergy to NSAIDs. Participants were identified 
by daily electronic lipase laboratory alerts, and by care teams in the emergency department, 
medical floor, intensive care unit (ICU), and pancreatobiliary consult service, who directly 
contacted the study team. Eligibility was determined by the principal investigator (GP). Eligible 
subjects were invited for enrollment by the study coordinator (PP, IP). All enrolled participants 
provided written informed consent. 
 
Statistical Considerations 
 
Descriptive statistics are reported as absolute values (percentage), mean ± standard deviation 
(SD), or median (interquartile range [IQR]), as appropriate. For the analysis of the primary 
endpoint, we used a two-sided Wilcoxon rank-sum test to analyze the difference in the change of 
SIRS scores between the treatment groups. Missing data of the primary outcome was handled 
using the last observation carried forward imputation method. Comparisons of baseline 
characteristics and secondary endpoints were evaluated using chi-square or Fisher’s exact tests 
for categorical data and t–test or Wilcoxon rank sum test for continuous data, as appropriate. 
Kaplan-Meier methodology was used to estimate the overall risk of organ failure in each 
treatment group. The log-rank test was used to test the difference in risk of organ failure between 
treatment arms. Patients were followed up until date of organ failure or censoring. All analyses 
were performed according to the intention-to-treat principle. Per-protocol analysis was also 
performed. Statistical significance was defined as P<0.05. 
 
 

SAP_001.pdf: 
 
 
 
 
ID: STUDY19050212 
 
 
June 1st, 2013 
 
 
A Randomized Controlled Pilot Trial of Indomethacin in Acute Pancreatitis 
 
 
NCT02692391 


Randomized 
Patients  
N = 42 
Completed 
N = 16 
Discontinued 
N = 2 
Indomethacin 
N = 18 
Completed 
N = 20 
Discontinued 
N =4 
Placebo 
N = 24 
Reasons for 
Discontinuation 
Adverse event 
0 
Withdrawal by subject 
2 
Physician Decision 
0 
Reasons for 
Discontinuation 
Adverse event 
0 
Withdrawal by subject 
2 
Physician Decision 
2 
Statistical Analysis Plan 
 
The sample size calculation was based on our prospective observational data on the incidence of SIRS among 
hospitalized patients with AP and on the assumption that a mean SIRS score reduction of 0.5 with a standard deviation of 0.64 
was clinically meaningful. We estimated that a sample size of 42 patients was needed to detect a difference of 0.5 in the SIRS 
change (baseline to 48h) between the indomethacin and placebo arms, with a power of 80% and a one-sided alpha of 0.05.  
 
Descriptive statistics are reported as absolute values (percentage), mean ± standard deviation (SD), or median 
(interquartile range [IQR]), as appropriate. For the analysis of the primary endpoint, we used a two-sided Wilcoxon rank-sum 
test to analyze the difference in the change of SIRS scores between the treatment groups. Missing data of the primary outcome 
was handled using the last observation carried forward imputation method. Comparisons of baseline characteristics and 
secondary endpoints were evaluated using chi-square or Fisher’s exact tests for categorical data and t–test or Wilcoxon rank 
sum test for continuous data, as appropriate. Kaplan-Meier methodology was used to estimate the overall risk of organ failure 
in each treatment group. The log-rank test was used to test the difference in risk of organ failure between treatment arms. 
Patients were followed up until date of organ failure or censoring. All analyses were performed according to the intention-to-
treat principle. Per-protocol analysis was also performed. Statistical significance was defined as P<0.05. 
 
 
Firgure 1: Enrollment, Randomization and Retention of Study Participants.