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

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Johns Hopkins University

Must not be taking: Tacrolimus, Immune modulators, NSAIDs

Disqualifiers: Pregnancy, Chronic pancreatitis, Kidney disease, others

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing if taking oral tacrolimus before a specific medical procedure can prevent pancreatitis. The study focuses on patients who are at risk of developing pancreatitis after this procedure. Tacrolimus works by stopping the release of substances in the pancreas that cause inflammation. Tacrolimus has been studied for its potential to prevent pancreatitis after this procedure by reducing inflammation.

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.

What data supports the effectiveness of the drug Indomethacin for preventing post-ERCP pancreatitis?

Research shows that rectal indomethacin is effective in preventing post-ERCP pancreatitis, especially in high-risk patients, as demonstrated in several studies and meta-analyses. ^{1 2 3 4 5}

Is the combination of Indomethacin and Tacrolimus generally safe for humans?

Indomethacin, a non-steroidal anti-inflammatory drug (NSAID), is known to cause stomach issues like ulcers and bleeding, but efforts are being made to reduce these side effects. Tacrolimus is an immunosuppressant used in organ transplants, and while specific safety data for the combination of these two drugs is not provided, both drugs have known side effects that should be considered. ^{6 7 8 9 10}

What makes the drug combination of Indomethacin and Tacrolimus unique for preventing post-ERCP pancreatitis?

The combination of Indomethacin and Tacrolimus is unique because it uses a rectal administration route for Indomethacin, which is not common for preventing post-ERCP pancreatitis, and combines it with Tacrolimus, an immunosuppressant, potentially offering a novel approach to reduce inflammation and prevent pancreatitis after ERCP (a procedure to examine the pancreatic and bile ducts). ^{11 12 13 14 15}

Research Team

Venkata S. Akshintala, M.D.

Principal Investigator

Johns Hopkins University

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Placebo (Drug)
• Rectal Indomethacin (Nonsteroidal Anti-inflammatory Drug (NSAID))
• Tacrolimus capsule (Calcineurin Inhibitor)

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.

Participant Groups

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 Canada for the following indications:

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+

Findings from Research

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]

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]

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]

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]

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 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]

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 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]

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]

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 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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Rectal indomethacin with topical epinephrine versus indomethacin alone for preventing Post-ERCP pancreatitis - A systematic review and meta-analysis. [2021]

2. United States 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. [2022]

3. United States 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. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Rectal Indomethacin Does Not Prevent Post-ERCP Pancreatitis in Consecutive Patients. [2022]

5. United States 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. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Anti-inflammatory indomethacin analogs endowed with preferential COX-2 inhibitory activity. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Gastrointestinal safety and therapeutic efficacy of parenterally administered phosphatidylcholine-associated indomethacin in rodent model systems. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacological evaluation and preliminary pharmacokinetics studies of a new diclofenac prodrug without gastric ulceration effect. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Upper GI mucosal effects of parecoxib sodium in healthy elderly subjects. [2013]

10. Germany pubmed.ncbi.nlm.nih.gov

A prostacyclin-sparing effect of indobufen vs. aspirin. [2013]

11. United States 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. [2014]

12. United States pubmed.ncbi.nlm.nih.gov

Ketorolac, prednisolone, and dexamethasone for postoperative inflammation. [2019]

13. France 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]. [2013]

14. Germany pubmed.ncbi.nlm.nih.gov

[Diclofenac-dexamethasone combination in treatment of postoperative inflammation: prospective double-blind study]. [2013]

15. United States pubmed.ncbi.nlm.nih.gov

A comparison of topical non-steroidal anti-inflammatory drugs to steroids for control of post cataract inflammation. [2014]