Safety and Tolerability of Pirfenidone in Acute Pancreatitis

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Pancreatitis, Acute

Intervention / Treatment
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* Drug: Pirfenidone Oral Tablet
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18 - 85 years of age Admitted to hospital for AP, defined by at least 2 of the following 3: amylase or lipase values, or both, that are greater than 3 times the upper limit of normal values characteristic cross-sectional imaging typical upper abdominal pain- acute onset of a persistent, severe, epigastric pain often radiating to the back Patients identified, approached, and consented to administer study medication or placebo within 48 hours of diagnosis of AP. Predicted to have MSAP or SAP by presence of one or more of the following criteria APACHE II ≥ 8 Modified Glasgow or Imrie score ≥ 3 CRP > 150 mg/dL PASS score > 140 at or within 48 hrs. of admission CT or MRI imaging suggesting pancreatic and/or peri-pancreatic necrosis Exclusion Criteria: Age < 18 or > 85 years Body weight > 200 kg Presentation to the medical attention > 48 h after diagnosis of AP Inability to recruit, randomize and start the allocated treatment within 48h of start of pain Ongoing AP or diagnosis of AP in previous 30 days Chronic pancreatitis Known hypersensitivity to pirfenidone AST/ALT ≥ 2 times the upper normal limit. Alkaline phosphatase ≥ 2 times the upper normal limit Bilirubin higher than upper normal limit Moderate to severe heart failure and/or coronary heart disease (New York Heart Association (NYHA) Functional Class III/IV) On home oxygen or home mechanical ventilation Advanced liver disease Paralytic ileus or significant nausea and vomiting Chronic Diarrhea Immunosuppressive disorder or on immunosuppressive medications Active or advanced malignancy Known cancer that is end-stage with ongoing palliative care or for which palliative care is appropriate Known established infection prior to the onset of acute pancreatitis Known history of infective hepatitis Known live vaccines or therapeutic infectious agents within one month of admission Known pregnancy or lactation at the time of admission Ongoing photosensitivity and rash 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. 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 Alcohol or substance abuse in the past 2 years Family or personal history of long QT syndrome ( > 500 msec) Medications like fluvoxamine or sildanefil Significant photosensitivity or new rash Renal disease with GFR < 30 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 Any condition that, in the opinion of the investigator, might be significantly exacerbated by the known side effects associated with the administration of pirfenidone

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo<br> | Drug: Placebo<br>* The placebo tablets will be an exact replica of the pirfenidone tablet.<br>|
| Experimental: Pirfenidone Treatment<br> | Drug: Pirfenidone Oral Tablet<br>* 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.<br>|

What is the study measuring?
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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 |