Safety and Tolerability of Pirfenidone in Acute Pancreatitis

Evaluation of Pirfenidone as a Therapy in Patients With Predicted Moderate to Severe Acute Pancreatitis

The goal of the current pilot clinical trial is to evaluate the safety and tolerability of pirfenidone in patients with predicted moderately severe and severe acute pancreatitis. Pirfenidone is currently approved by FDA for the treatment of idiopathic pulmonary fibrosis. Now, over 5 years of data has accumulated demonstrating safety of its use in humans. The investigators' preclinical data suggest that pirfenidone is very effective in reducing the severity of acute pancreatitis in animal models. Following are the objectives of the proposed clinical trial:

Primary Objective:

• To evaluate the safety and tolerability of pirfenidone, compared to placebo, in patients predicted to have moderately severe or severe AP.
• To evaluate the efficacy of pirfenidone in reducing the laboratory markers of inflammation and improving patient reported outcome measures.

Secondary Objective:

- To evaluate the efficacy of pirfenidone in reducing the severity of acute pancreatitis, as measured by well-defined endpoints.

Study Overview

• Status: Recruiting
• Conditions: Pancreatitis, Acute
• Intervention / Treatment: Drug: Placebo; Drug: Pirfenidone Oral Tablet

Detailed Description

The study is a Randomized Pilot clinical trial evaluating safety and tolerability of pirfenidone in patients with predicted moderately severe to severe acute pancreatitis. There are built in secondary end-points for efficacy. The patients with acute pancreatitis, who present within 48h of establishment of the diagnosis, will be screened for exclusion and inclusion criteria and consented for the clinical trial. Patients with be randomized into placebo or pirfenidone arm and followed daily in-person, while in hospital, and by telephone once discharged from the hospital (weekly for 4 weeks, then monthly for up to 6 months) for study end points.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Vikas Dudeja, MD; Phone Number: 205 975 7836; Email: vdudeja@uabmc.edu
• Study Contact Backup: Name: Mustafa AL-Oabidi, MD; Phone Number: 2054139974; Email: malobaidi@uabmc.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Recruiting
      • UAB
      • Contact: Vikas Dudeja, MD; Phone Number: 205-975-7836; Email: vdudeja@uabmc.edu
      • Contact: Mustafa Al-Obaidi, MD; Phone Number: 205 413 9974; Email: malobaidi@uabmc.edu
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic
      • Contact: Santhi Swaroop Vege, MD; Phone Number: 507.255.5713; Email: Vege.Santhi@mayo.edu
      • Contact: Vincent Anani; Phone Number: 507.255.5713; Email: anani.vincent@mayo.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients 18 - 85 years of age

2. Admitted to hospital for AP, defined by at least 2 of the following 3:

   1. amylase or lipase values, or both, that are greater than 3 times the upper limit of normal values
   2. characteristic cross-sectional imaging
   3. typical upper abdominal pain- acute onset of a persistent, severe, epigastric pain often radiating to the back
3. Patients identified, approached, and consented to administer study medication or placebo within 48 hours of diagnosis of AP.

4. Predicted to have MSAP or SAP by presence of one or more of the following criteria

   1. APACHE II ≥ 8
   2. Modified Glasgow or Imrie score ≥ 3
   3. CRP > 150 mg/dL
   4. PASS score > 140 at or within 48 hrs. of admission
   5. CT or MRI imaging suggesting pancreatic and/or peri-pancreatic necrosis

Exclusion Criteria:

1. Age < 18 or > 85 years
2. Body weight > 200 kg
3. Presentation to the medical attention > 48 h after diagnosis of AP
4. Inability to recruit, randomize and start the allocated treatment within 48h of start of pain
5. Ongoing AP or diagnosis of AP in previous 30 days
6. Chronic pancreatitis
7. Known hypersensitivity to pirfenidone
8. AST/ALT ≥ 2 times the upper normal limit.
9. Alkaline phosphatase ≥ 2 times the upper normal limit
10. Bilirubin higher than upper normal limit
11. Moderate to severe heart failure and/or coronary heart disease (New York Heart Association (NYHA) Functional Class III/IV)
12. On home oxygen or home mechanical ventilation
13. Advanced liver disease
14. Paralytic ileus or significant nausea and vomiting
15. Chronic Diarrhea
16. Immunosuppressive disorder or on immunosuppressive medications
17. Active or advanced malignancy
18. Known cancer that is end-stage with ongoing palliative care or for which palliative care is appropriate
19. Known established infection prior to the onset of acute pancreatitis
20. Known history of infective hepatitis
21. Known live vaccines or therapeutic infectious agents within one month of admission
22. Known pregnancy or lactation at the time of admission
23. Ongoing photosensitivity and rash
24. Women of childbearing potential who are not on oral or injectable contraceptives or IUDs and do not consent to practice abstinence for period of 4 weeks.
25. Known to be currently participating in a trial testing any investigational medicinal product or participation in a clinical study involving a medicinal product in the last three months
26. Alcohol or substance abuse in the past 2 years
27. Family or personal history of long QT syndrome ( > 500 msec)
28. Medications like fluvoxamine or sildanefil
29. Significant photosensitivity or new rash
30. Renal disease with GFR < 30
31. Any condition other than above that, in the opinion of the investigator, is likely to result in the death of the patient within the next 2 years
32. Any condition that, in the opinion of the investigator, might be significantly exacerbated by the known side effects associated with the administration of pirfenidone

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo	Drug: Placebo; The placebo tablets will be an exact replica of the pirfenidone tablet.
Experimental: Pirfenidone Treatment	Drug: Pirfenidone Oral Tablet; Patients in the pirfenidone treatment arm will be given pirfenidone 267mg tablet, tid for 1 day followed by dose escalation to two 267 mg tablet tid for 6 days. Thus, the treatment will be for total of 7 days or till patients develop an adverse event that requires their participation in the study to be stopped.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Development of anticipated or un-anticipated serious adverse events (class 3 or 4)	Development of anticipated or un-anticipated serious adverse events (class 3 or 4)	6 months
percentage of patients starting and completion of the planned drug treatment	percentage of patients starting and completion of the planned drug treatment	7 days
Changes in C-reactive protein (CRP), TNF-α, interleukin (IL)-6, IL-8 and IL-10 levels	Compared to base line	7 days
percentage of patients having decrease in PAN-PROMISE score by at least 10 points at 72h after initiation of the drug	Measurement of PAN-PROMISE score	3 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cumulative PAN-PROMISE score	total of the PAN-PROMISE over 7 days	7
cumulative PASS score	total of PASS score during admission	duration of admission
PASS score at the time of discharge	PASS score measurement	duration of admission
Composition outcome	total of development of new or worsening pancreatic or peri-pancreatic necrosis, death or major infection	6 months
Readmission and/or ER visits		within 30 days and within 6 months

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Mayo Clinic

Publications and helpful links

General Publications

• Palathingal Bava E, George J, Tarique M, Iyer S, Sahay P, Gomez Aguilar B, Edwards DB, Giri B, Sethi V, Jain T, Sharma P, Vaish U, C Jacob HK, Ferrantella A, Maynard CL, Saluja AK, Dawra RK, Dudeja V. Pirfenidone increases IL-10 and improves acute pancreatitis in multiple clinically relevant murine models. JCI Insight. 2022 Jan 25;7(2):e141108. doi: 10.1172/jci.insight.141108.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2023
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: March 23, 2022
• First Submitted That Met QC Criteria: April 23, 2022
• First Posted (Actual): April 28, 2022

Study Record Updates

• Last Update Posted (Estimated): August 31, 2023
• Last Update Submitted That Met QC Criteria: August 28, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pancreatic Diseases; Pancreatitis; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Pirfenidone
• Other Study ID Numbers: IRB-300008875

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No