Pirfenidone as Treatment of Chronic Pancreatitis

This is a multi-institutional, double-blind, placebo-controlled clinical trial of the safety, tolerability and efficacy of Pirfenidone in patients with CP. Patients with a confirmed diagnosis of CP will be randomly assigned to Pirfenidone or placebo (2:1 randomization). The assigned allocation (drug or placebo) will be continued for 48 weeks.

Subjects will be asked to complete questionnaires, have blood draws, and will be randomized to either the IP or placebo. They will have both in person and telephone/remote visits.

All subjects will be diagnosed with chronic pancreatitis (CP).

Inclusion criteria

• Patients 18 - 85 years of age
• Diagnosis of CP, based on at least one of the following on CT and/or MRI/MRCP:

• Pancreatic parenchymal and/or ductal calcification
• Unequivocal CP on imaging (Tirkes et al3) (Cambridge grade 3 or grade 4)
• Average pain of >/=4 (on a 0-10 scale) related to pancreatitis in the past three months [regardless of the use of pain medications (opioids or non-opioids)] and/or evidence of ongoing pancreatic inflammatory activity, with an inflammatory pancreatic flare occurring one or more times within the past six months [inflammatory pancreatic flare is defined as an exacerbation of pancreatic pain in combination with one or more of the following: 1) plasma amylase/lipase levels elevated 2-folds or more than the upper limit of normal; 2) elevated plasma levels of CRP 2-fold or more than the upper normal level without suspicion of other sources such as infection; 3) signs of pancreatic inflammation on cross-sectional imaging]
• Ability to understand and the willingness to sign a written informed consent document and medical release
• Willing and able to comply with trial protocol and follow up

Exclusion criteria

• Age < 18 or > 85 years
• Pancreatic endotherapy and/or pancreatic surgery and/or celiac plexus block or neurolysis in last 3 months.
• Known hypersensitivity to Pirfenidone
• AST and/or ALT > times the upper normal limit
• Bilirubin higher than 1.5 times the 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 mechanical ventilation
• Clinically diagnosed cirrhosis
• Significant nausea and/or vomiting preventing administration of light diet
• Chronic diarrhea (>6 months, 3 or more stools/day, which in investigator's opinion is not due to pancreatic exocrine insufficiency)
• Active cancer (on chemotherapy, radiation or other treatment of cancer) or < 3 years cancer free (non-melanoma skin cancers are not exclusion)
• Active hepatitis C
• Known history of hepatitis B
• Ongoing photosensitivity and rash
• Known live vaccines or therapeutic infectious agents within one month of potential enrollment
• Known pregnancy or lactation at the time of enrollment
• Women of childbearing potential who are not on oral or injectable contraceptives or not using an Intrauterine device (IUD), and do not consent to adequate contraception while on, and for 90 days after the administration of the drug/placebo
• Currently enrolled in, or has participated in, a clinical trial involving an investigational medicinal product within the past three months (if patients who have participated in a clinical trial involving an investigation medication product are included, they will only be included if they are beyond 5 half-lives from the last dose, and if there is a relevant assay available, there will be undetectable drug levels).
• Ongoing substance use which in the opinion of the investigator may affect their participation or compliance with the study protocol
• Alcohol consumption more than 7 drinks per week for females and more than 14 drinks per week for males.
• Family or personal history of long QT syndrome (> 500 msec)
• Currently using strong (e.g., fluvoxamine, enoxacin) or moderate (e.g., ciprofloxacin) CYP1A2 Inhibitors. If the patient is able to consult with their prescriber and switch to an alternative medication that is not a CYP1A2 inhibitor, they may be eligible for inclusion in the clinical trial. Any patient who stops a CYP1A2 inhibitor to be enrolled in the clinical trial, we will wait for 7 days or 5 half-lives (whichever is longer) before the study drug is started.
• Patients taking strong CYP1A2 inducers, namely Albendazole, Carbamazepine, Primidone and Rifampin, and who cannot stop these drugs safely, will be excluded. If patients could stop these medications, they could be recruited into the study, either 14-days or 5-half lives (whichever is longer) after stopping the study drug.
• Glomerular Filtration Rate < 60
• Life expectancy of less than 2 years in the opinion of the investigator
• Any medical condition that, in the opinion of the investigator, might be significantly exacerbated by the known side effects associated with the administration of pirfenidone.

All participants of childbearing potential, except if post-menopausal [see definition of menopause below] or had a hysterectomy, bilateral tubal ligation/clip (surgical sterilization) or surgical removal of both the ovaries), must have a negative urine pregnancy test documented within 2 days prior to initiation of the study drug.

Menopause can be assumed to have occurred when there is either:

A) Either twelve [12] months of spontaneous amenorrhea; or B) six [6] months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL; or C) six [6] weeks postsurgical bilateral oophorectomy with or without hysterectomy.

Hormonal deficiency will be documented in the case of suspected spontaneous menopause as follows:

• If age >54 years and with the absence of normal menses: Serum FSH (Follicle Stimulating Hormone) level elevated to within the post-menopausal range based on the laboratory reference range where the hormonal assay is performed;
• If age <54 years and with the absence of normal menses: Negative serum or urine -Human Chorionic Gonadotropin (HCG) with concurrently elevated serum FSH (Follicle Stimulating Hormone) level in the post-menopausal range, depressed estradiol (E2) level in the post-menopausal range, and absent serum progesterone level, based on the laboratory reference ranges where the hormonal assays are performed