Clinical trial NCT05350371: Safety and Tolerability of Pirfenidone in Acute Pancreatitis
Official title: Evaluation of Pirfenidone as a Therapy in Patients With Predicted Moderate to Severe Acute Pancreatitis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Pancreatitis, Acute
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: Mayo Clinic
First posted: 2022-04-28
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Development of anticipated or un-anticipated serious adverse events (class 3 or 4)
timeFrame: 6 months
measure: percentage of patients starting and completion of the planned drug treatment
timeFrame: 7 days
measure: Changes in C-reactive protein (CRP), TNF-α, interleukin (IL)-6, IL-8 and IL-10 levels
timeFrame: 7 days
measure: percentage of patients having decrease in PAN-PROMISE score by at least 10 points at 72h after initiation of the drug
timeFrame: 3 days
Secondary outcomes:
measure: cumulative PAN-PROMISE score
timeFrame: 7
measure: cumulative PASS score
timeFrame: duration of admission
measure: PASS score at the time of discharge
timeFrame: duration of admission
measure: Composition outcome
timeFrame: 6 months
measure: Readmission and/or ER visits
timeFrame: within 30 days and within 6 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: UAB
state: Alabama
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
References:
citation: 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.