Acute PancreatitisPhase 3NCT02692391
A Randomized Controlled Pilot Trial of Indomethacin in Acute Pancreatitis
A Phase 3 study testing Indomethacin in people with Acute Pancreatitis, run by University of Pittsburgh at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Pancreatitis
- What is being tested?
- Indomethacin
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 42 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2013to 30 Dec 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- All patients ages 18 or above admitted to UPMC with a diagnosis of AP based on at least 2 of the following criteria:
- 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
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Univeristy of Pittsburgh
Pittsburgh, Pennsylvania, 15213
About this study
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.
Read the 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.
- Conditions
- Acute Pancreatitis
- Being tested
- Indomethacin, Placebo
- Keywords
- Acute pancreatitis, Indomethacin, Organ failure, Prevention
- Medical subject headings
- Pancreatitis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IndomethacinDrug
Also called Indocin
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.
PlaceboDrug
Also called Glycerin
Glycerin placebo suppositories which are identical in shape, size, color, and packaging to rectal indomethacin
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | 6 doses, Q8hrs for a total period of 48 hours Receives: Drug: Placebo |
| Indomethacin suppository | Active comparator | Loading dose :100mg Maintenance dose: 50 mg, Q8hrs for a total period of 48 hours (5 doses) Receives: Drug: Indomethacin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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).
Measured: 48 hours
Secondary outcomes (2)
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.
Measured: 7 days
Mortality
Enrolled subjects that died. A death indicates a worse outcome.
Measured: 1 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Feb 2016 (estimated)
- Study startJul 2013
- Primary completion19 Jul 2019
- Study completion30 Dec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Acute PancreatitisStudies of the same condition, open and under way.
- More trials run by University of PittsburghThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 42 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pittsburgh
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, David Whitcomb, University of Pittsburgh
- Investigators
- Georgios I Papachristou, MD PhD, Study chair, Ohio State University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02692391
- Sponsor's protocol ID
- STUDY19050212
- Status last verified
- Mar 2021
- First submitted
- 15 Feb 2016
- Last updated
- 22 Apr 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 24513806Freeman 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.
PubMed 15173799Machicado 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.
PubMed 34704970
Study at a glance
From the registry record, last updated by the sponsor on 22 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Controlled Pilot Trial of Indomethacin in Acute Pancreatitis
- ClinicalTrials.gov ID
- NCT02692391
- Acronym / sponsor ID
- STUDY19050212
- Conditions
- Acute Pancreatitis
- Keywords
- Acute pancreatitis, Indomethacin, Organ failure, Prevention
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 42 participants (actual)
- Lead sponsor
- University of PittsburghUniversity, hospital or other
- Study start
- Jul 2013 (actual)
- Primary completion
- 19 Jul 2019 (actual)
- Study completion
- 30 Dec 2019 (actual)
- First posted
- 26 Feb 2016 (estimated)
- Results
- Posted 22 Apr 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: Placebo6 doses, Q8hrs for a total period of 48 hours |
| Indomethacin suppository | Active comparator | Drug: IndomethacinLoading dose :100mg Maintenance dose: 50 mg, Q8hrs for a total period of 48 hours (5 doses) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- All patients ages 18 or above admitted to UPMC with a diagnosis of AP based on at least 2 of the following criteria:
- 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
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IndomethacinAlso: IndocinRectal 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. | Drug | Indomethacin suppository |
| PlaceboAlso: GlycerinGlycerin placebo suppositories which are identical in shape, size, color, and packaging to rectal indomethacin | Drug | Placebo |
Primary outcome
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).
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).
2 secondary outcomes
Number of Participants Who Development of Organ Failure
Time frame: 7 days
Mortality
Time frame: 1 month
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Apr 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 24513806Sotoudehmanesh 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.
- Results publication: PubMed 15173799Freeman 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.
- Derived from this study: PubMed 34704970Machicado 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Georgios I Papachristou, MD PhD study chair
Ohio State University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Indomethacin in people with Acute Pancreatitis, run by University of Pittsburgh at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Apr 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Systemic Inflammatory Response Syndrome (SIRS) Score (time frame: The change in the SIRS score (48 hours - baseline)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02692391, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Apr 2021.