Indomethacin + Tacrolimus to Prevent Post-ERCP Pancreatitis

(INTRO Trial)

Recruiting at 5 trial locations

Overseen By Venkata S. Akshintala, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Johns Hopkins University

Must not be taking: Tacrolimus, Immune modulators, NSAIDs

Disqualifiers: Pregnancy, Chronic pancreatitis, Kidney disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 1 day

4874 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether taking tacrolimus, an immunosuppressant drug, before a specific type of endoscopy known as ERCP, can prevent pancreatitis, a painful inflammation of the pancreas, after the procedure. Participants will take either tacrolimus or a placebo (a pill with no active drug) before the procedure, along with rectal indomethacin, administered immediately after. Individuals undergoing an ERCP at one of the participating centers, who do not have certain conditions like chronic pancreatitis or recent acute pancreatitis, may be suitable for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are already using tacrolimus or immune modulators.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that both tacrolimus and rectal indomethacin are generally safe for people. Tacrolimus, a type of medication, has been studied for its ability to prevent pancreatitis, which is inflammation of the pancreas, after a specific type of endoscopy called ERCP. One study found that patients tolerated it well and did not experience serious side effects.

Rectal indomethacin is an anti-inflammatory medicine that studies have shown can significantly reduce the risk of pancreatitis for people undergoing an ERCP. Most people handle it well without major issues.

While both treatments appear safe overall, discussing any concerns with a doctor before joining a clinical trial is always important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for preventing post-ERCP pancreatitis because it combines tacrolimus, an immunosuppressant, with rectal indomethacin, a non-steroidal anti-inflammatory drug (NSAID), offering a potentially more effective approach. Unlike the standard care options that typically involve NSAIDs alone, this combination aims to reduce pancreatic inflammation by targeting the immune response, potentially lowering the risk of pancreatitis more effectively. Additionally, the use of rectal administration for indomethacin can provide direct and rapid delivery to the affected area, which may enhance its effectiveness in high-risk patients.

What evidence suggests that this trial's treatments could be effective for preventing post-ERCP pancreatitis?

This trial will compare the effectiveness of two treatment combinations in preventing post-ERCP pancreatitis. Studies have shown that oral tacrolimus can safely help prevent pancreatitis, which is inflammation of the pancreas, after an ERCP. An ERCP is a procedure that examines the pancreas and bile ducts. In this trial, one group will receive oral tacrolimus combined with rectal indomethacin, which research suggests further lowers the risk of pancreatitis. Another group will receive a placebo capsule with rectal indomethacin. Research has proven that using rectal indomethacin alone decreases the chances of pancreatitis after ERCP. These findings strongly support using these treatments to help prevent pancreatitis after ERCP. ^{1 2 3 4 6}

Who Is on the Research Team?

Venkata S. Akshintala, M.D.

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for adults undergoing ERCP at participating centers who can consent. It's not for those with certain pancreas or kidney conditions, pregnant or breastfeeding women, people allergic to tacrolimus/NSAIDs, or those currently on immune modulators.

Inclusion Criteria

I am over 18 and agree to an ERCP procedure at a participating center.

Exclusion Criteria

I have had acute pancreatitis within a month after an ERCP procedure.

I have had a procedure to open my bile duct but don't expect a pancreas duct imaging.

My cancer is located in the head of the pancreas.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment

Participants receive either oral tacrolimus or placebo 1-2 hours prior to ERCP, followed by rectal indomethacin immediately after ERCP

1 day

1 visit (in-person)

Follow-up

Participants are monitored for the development and severity of post-ERCP pancreatitis

30 days

Follow-up visits as needed

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Rectal Indomethacin
• Tacrolimus capsule

Trial Overview The study tests if oral tacrolimus before an ERCP procedure can prevent post-ERCP pancreatitis compared to a placebo. Participants will receive either the drug or a placebo in a controlled environment.

How Is the Trial Designed?

Group I: Oral Tacrolimus + Indomethacin Experimental Treatment 2 Interventions

* Tacrolimus Capsule 1-2 hours prior to the endoscopy * Rectal Indomethacin immediately after ERCP, in high-risk patients

Group II: Oral Placebo + Indomethacin Placebo Group 2 Interventions

* Placebo Capsule 1-2 hours prior to the endoscopy * Rectal Indomethacin immediately after ERCP, in high-risk patients

Rectal Indomethacin is already approved in United States, Canada for the following indications:

Approved in United States as Indocin for:

• Acute pain
• Rheumatoid arthritis
• Ankylosing spondylitis
• Osteoarthritis
• Bursitis
• Gouty arthritis
• Patent ductus arteriosus

Approved in Canada as Indocid for:

• Moderate to severe arthritis
• Gout
• Ankylosing spondylitis
• Bursitis
• Tendinitis

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

Published Research Related to This Trial

In a study involving 58 patients after cataract surgery, ketorolac tromethamine 0.5% and diclofenac sodium 0.1% were found to be as effective as prednisolone acetate 1% in reducing inflammation, as measured by flare and cell counts.

All three treatments showed no significant differences in intraocular pressure or any medication-related complications, indicating that ketorolac and diclofenac are safe alternatives to prednisolone for post-surgery care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized double-masked trial comparing ketorolac tromethamine 0.5%, diclofenac sodium 0.1%, and prednisolone acetate 1% in reducing post-phacoemulsification flare and cells. el-Harazi, SM., Ruiz, RS., Feldman, RM., et al.[2014]

The prodrug 1-(2,6-dichlorophenyl)indolin-2-one shows significant anti-inflammatory effects similar to diclofenac but without causing gastric ulceration, making it a safer long-term NSAID option.

This prodrug effectively reduces levels of PGE(2), COX-2 expression, and cellular influx in inflammation models, indicating its potential for treating inflammatory conditions without the common side effects associated with traditional NSAIDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological evaluation and preliminary pharmacokinetics studies of a new diclofenac prodrug without gastric ulceration effect. Santos, JL., Moreira, V., Campos, ML., et al.[2021]

In a systematic review of 3 randomized controlled trials involving 2244 patients, the combination of rectal indomethacin and topical epinephrine did not show any significant advantage over rectal indomethacin alone in preventing post-ERCP pancreatitis (PEP).

The study found no differences in mortality or overall adverse events between the two treatment groups, indicating that adding topical epinephrine does not enhance safety or efficacy in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rectal indomethacin with topical epinephrine versus indomethacin alone for preventing Post-ERCP pancreatitis - A systematic review and meta-analysis. Aziz, M., Ghanim, M., Sheikh, T., et al.[2021]

In a study of 40 patients, the combination of dexamethasone acetate and diclofenac drops significantly reduced inflammation in the anterior chamber after cataract surgery, showing faster results compared to dexamethasone with placebo, especially notable at days 3 and 12.

The combination treatment was well-tolerated, with no significant differences in side effects compared to the placebo, indicating it is a safe option for post-operative care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Diclofenac-dexamethasone combination in treatment of postoperative inflammation: prospective double-blind study]. Othenin-Girard, P., Borruat, X., Bovey, E., et al.[2013]

In a study involving healthy elderly subjects aged 65-75, parecoxib sodium showed no incidence of gastric or duodenal ulcers, indicating its safety and tolerability over 7 days of treatment.

In contrast, ketorolac resulted in a significant incidence of ulcers and erosions, with 23% of subjects developing at least one ulcer, highlighting parecoxib's lower risk of gastroduodenal mucosal injury compared to ketorolac.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Upper GI mucosal effects of parecoxib sodium in healthy elderly subjects. Stoltz, RR., Harris, SI., Kuss, ME., et al.[2013]

A new indole derivative, compound 4f, demonstrated superior anti-inflammatory effects and a much safer profile compared to traditional indomethacin, achieving 90.5% edema inhibition with a low ulcerogenic liability.

Compound 4f selectively inhibited COX-2 over COX-1, with a selective index of 65.71, indicating its potential as a safer alternative for treating inflammation without the severe gastric damage associated with indomethacin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-inflammatory indomethacin analogs endowed with preferential COX-2 inhibitory activity. Amin, NH., El-Saadi, MT., Hefny, AA., et al.[2023]

In a 6-week study involving 157 patients undergoing cataract surgery, ketorolac was found to be as effective as glucocorticoids in reducing signs of anterior-segment inflammation, such as cells and flare in the anterior chamber.

Ketorolac demonstrated superior efficacy compared to glucocorticoids in preventing blood-aqueous barrier breakdown at early postoperative time points, suggesting it can be a viable alternative for managing postoperative inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketorolac, prednisolone, and dexamethasone for postoperative inflammation. Ostrov, CS., Sirkin, SR., Deutsch, WE., et al.[2019]

In a study involving 352 patients, LCM 1110 eyedrops (0.1% indomethacin) demonstrated similar efficacy in managing post-cataract surgery inflammation compared to standard 0.1% indomethacin and 0.1% diclofenac, with no significant differences in inflammation markers or visual acuity.

LCM 1110 was better tolerated than diclofenac, with fewer instances of superficial punctate keratitis and improved patient comfort during instillation, indicating it may be a safer option for postoperative care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Double-blind study on 3 parallel groups of 2 formulations of 0.1% indomethacin and 0.1% diclofenac in preventing and controlling inflammation after cataract surgery]. Arnaud, B., Trinquand, C.[2013]

The combination of phosphatidylcholine with indomethacin (INDO-PC) significantly reduces gastrointestinal toxicity, such as bleeding and intestinal injury, compared to indomethacin alone, based on studies in rats.

Despite the reduced GI side effects, INDO-PC maintains similar levels of bioavailability and therapeutic effects, including analgesia and anti-inflammatory action, making it a promising alternative for parenteral use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal safety and therapeutic efficacy of parenterally administered phosphatidylcholine-associated indomethacin in rodent model systems. Lichtenberger, L., Romero, JJ., Dial, EJ.[2021]

Indobufen (indo) shows a similar ability to inhibit platelet function as aspirin (ASA) but has a significantly lower impact on the production of prostacyclin (6-keto-PGF1 alpha), which may lead to a better safety profile.

In a study involving 15 patients with ischemic heart disease and 10 healthy volunteers, indobufen demonstrated less inhibition of 6-keto-PGF1 alpha compared to ASA, suggesting that indo may provide effective platelet inhibition with reduced risk of side effects related to vascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prostacyclin-sparing effect of indobufen vs. aspirin. De Caterina, R., Giannessi, D., Bernini, W., et al.[2013]

In a study of 50 patients who underwent cataract surgery, diclofenac sodium 0.1% eye drops were found to be as effective as prednisolone acetate 1.0% eye drops in reducing postoperative inflammation.

Postoperative inflammation was assessed at multiple time points (one day, one week, and one month) using both clinical evaluation and objective measurement, showing no significant difference in effectiveness between the two treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of topical non-steroidal anti-inflammatory drugs to steroids for control of post cataract inflammation. Brennan, KM., Brown, RM., Roberts, CW.[2014]

Indomethacin suppositories, which are effective in preventing post-ERCP pancreatitis (PEP), were under-utilized in clinical practice, with usage remaining below 50% in 2018 despite evidence supporting their benefit.

The overall rate of PEP remained unchanged at 8.6% from 2009 to 2018, which may be linked to the low adoption of indomethacin and a significant decline in pancreatic duct stent usage during the same period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Practice Patterns in the Era of Rectal Indomethacin for Prophylaxis Against Post-ERCP Pancreatitis in a High-Risk Cohort. Smith, ZL., Elmunzer, BJ., Cooper, GS., et al.[2022]

Rectal indomethacin significantly reduces the incidence of post-ERCP pancreatitis (PEP) in high-risk patients, with a relative risk of 0.43, based on a meta-analysis of 8 trials involving 3778 participants.

In contrast, rectal indomethacin does not show a significant protective effect against PEP in average-risk patients, indicating that its benefits are primarily limited to those at higher risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rectal indomethacin is protective against post-ERCP pancreatitis in high-risk patients but not average-risk patients: a systematic review and meta-analysis. Inamdar, S., Han, D., Passi, M., et al.[2022]

In a randomized controlled trial involving 449 patients undergoing ERCP, rectal indomethacin did not significantly reduce the incidence of post-ERCP pancreatitis compared to a placebo, with rates of 7.2% in the indomethacin group and 4.9% in the placebo group (P = .33).

The study was stopped early due to futility, indicating that the use of rectal indomethacin as a preventive measure for pancreatitis in both high-risk and average-risk patients undergoing ERCP may not be effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rectal Indomethacin Does Not Prevent Post-ERCP Pancreatitis in Consecutive Patients. Levenick, JM., Gordon, SR., Fadden, LL., et al.[2022]

In a study of 192 high-risk patients undergoing ERCP, the combination of rectal indomethacin (IND) and lactated Ringer's solution (LR) significantly reduced the incidence of post-ERCP pancreatitis (PEP) to 6%, compared to 21% in the normal saline plus placebo group.

Patients receiving LR + IND also had lower readmission rates (2%) compared to those receiving normal saline plus placebo (13%), indicating that this treatment combination may enhance patient safety and recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lactated Ringer's solution in combination with rectal indomethacin for prevention of post-ERCP pancreatitis and readmission: a prospective randomized, double-blinded, placebo-controlled trial. Mok, SRS., Ho, HC., Shah, P., et al.[2022]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa1111103

A Randomized Trial of Rectal Indomethacin to Prevent ... Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10576534/

Rectal Indomethacin Dose Escalation (RIDE) for Prevention of ... Although rectal indomethacin (100mg) is effective in reducing the frequency and severity of post-endoscopic retrograde cholangiopancreatography (ERCP) ...

3. gut.bmj.com gut.bmj.com/content/74/7/1094

a multicentre, double-blind, randomised, controlled trial Some high-quality randomised controlled trials (RCT) have suggested 100 mg rectal indomethacin and diclofenac were efficacious in preventing ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01912716

Rectal Indomethacin in the Prevention of Post-ERCP ... The purpose of this study is to determine whether a dose of 200 mg, administered as rectal suppositories, is more effective than the standard dose of 100 mg.

5. journals.lww.com journals.lww.com/ajg/fulltext/2025/10002/s198_indomethacin_does_not_reduce_risk_of.199.aspx

S198 Indomethacin Does Not Reduce Risk of Post-ERCP ... Patients treated with indomethacin were older and had lower rates of pancreatitis risk factors (P < 0.001) as compared to controls. Patients undergoing ERCP who ...

6. karger.com karger.com/ddi/article/doi/10.1159/000548343/934278/Rectal-Indomethacin-in-Preventing-Post-Endoscopic

Rectal Indomethacin in Preventing Post-Endoscopic ... Rectal indomethacin significantly reduced the incidence of PEP compared to placebo (risk ratio [RR]: 0.58; 95% confidence interval [CI], 0.45– ...