Chronic Pancreatitis
Conditions
Keywords
Chronic Pancreatitis, Pancreatitis
Brief summary
The proposed project is focused towards evaluation of Pirfenidone as a novel therapeutic strategy in patients with chronic pancreatitis (CP).
Detailed description
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.
Interventions
Oral tablets taken with food three times daily. Titrated over 14 days: one tablet three times daily in week 1, two tablets three times daily in week 2, and three tablets three times daily (801 mg three times daily) from week 3 onward. Continued for 48 weeks unless reduced or interrupted to manage an adverse event. Dispensed by Investigational Drug Services according to the randomization code.
DRUGPlacebo
Matching placebo tablets, identical in appearance and packaging to the pirfenidone tablets to maintain double blinding. Administered on the same schedule: one tablet three times daily in week 1, two in week 2, and three from week 3 onward, taken with food, for a total of 48 weeks. Dispensed by Investigational Drug Services according to the randomization code.
OTHERPROMIS-Global Health
Patient-reported outcome instrument administered to all participants in both arms to assess health-related quality of life. Completed by the participant at Weeks 0, 4, 12, 24, 36, 48, 60, 72, 84 and 96, and at Early Termination.
OTHERComprehensive Pain Assessment Tool
Patient-reported outcome instrument administered to all participants in both arms to assess perceived pain. Completed by the participant at Weeks 0, 4, 12, 24, 36, 48, 60, 72, 84 and 96, and at Early Termination.
OTHERBrief Pain Inventory
Patient-reported outcome instrument administered to all participants in both arms. Administered once per visit and used for two purposes: the pain severity items assess perceived pain, and the pain interference items assess ability to participate in social roles and activities. Completed by the participant at Weeks 0, 4, 12, 24, 36, 48, 60, 72, 84 and 96, and at Early Termination.
OTHERPancreatitis Quality of Life Instrument
Patient-reported outcome instrument administered to all participants in both arms to assess ability to participate in social roles and activities. Completed by the participant at Weeks 0, 4, 12, 24, 36, 48, 60, 72, 84 and 96, and at Early Termination.
Sponsors
Vikas Dudeja
United States Department of Defense
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-blind, placebo-controlled clinical trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
All subjects will be diagnosed with chronic pancreatitis (CP). Inclusion Criteria: 1. Patients 18 - 85 years of age 2. Diagnosis of CP, based on at least one of the following on CT and/or MRI/MRCP: 1. Pancreatic parenchymal and/or ductal calcification 2. Unequivocal CP on imaging (Tirkes et al3) (Cambridge grade 3 or grade 4) 3. 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 \[inflammatory pancreatic flare is defined as an exacerbation of pancreatic pain in combination with one or more of the following: 1) plasma amylase/lipase levels elevated 2-folds or more than the upper limit of normal; 2) elevated plasma levels of CRP 2-fold or more than the upper normal level without suspicion of other sources such as infection; 3) signs of pancreatic inflammation on cross-sectional imaging\] 4. Ability to understand and the willingness to sign a written informed consent document and medical release 5. Willing and able to comply with trial protocol and follow up
Exclusion criteria
1. Age \< 18 or \> 85 years 2. Pancreatic endotherapy and/or pancreatic surgery and/or celiac plexus block or neurolysis in last 3 months. 3. Known hypersensitivity to Pirfenidone 4. AST and/or ALT \> times the upper normal limit 5. Bilirubin higher than 1.5 times the upper normal limit 6. Moderate to severe heart failure and/or coronary heart disease (New York Heart Association (NYHA) Functional Class III/IV) 7. On home oxygen or mechanical ventilation 8. Clinically diagnosed cirrhosis 9. Significant nausea and/or vomiting preventing administration of light diet 10. Chronic diarrhea (\>6 months, 3 or more stools/day, which in investigator's opinion is not due to pancreatic exocrine insufficiency) 11. Active cancer (on chemotherapy, radiation or other treatment of cancer) or \< 3 years cancer free (non-melanoma skin cancers are not exclusion) 12. Active hepatitis C 13. Known history of hepatitis B 14. Ongoing photosensitivity and rash 15. Known live vaccines or therapeutic infectious agents within one month of potential enrollment 16. Known pregnancy or lactation at the time of enrollment 17. 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 18. 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). 19. Ongoing substance use which in the opinion of the investigator may affect their participation or compliance with the study protocol 20. Alcohol consumption more than 7 drinks per week for females and more than 14 drinks per week for males. 21. Family or personal history of long QT syndrome (\> 500 msec) 22. 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. 23. 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. 24. Glomerular Filtration Rate \< 60 25. Life expectancy of less than 2 years in the opinion of the investigator 26. 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: 1. 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; 2. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least One Grade 3 or Grade 4 Adverse Event as Assessed by CTCAE Version 5.0 | From first dose of study drug through Week 48 | Adverse events will be assessed and graded using a modified Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, which grades events from Grade 1, mild, to Grade 5, death related to adverse event. A participant is counted once if one or more adverse events of Grade 3 or Grade 4 are recorded during the treatment period, regardless of how many such events occur. The proportion of participants meeting this criterion will be compared between the pirfenidone and placebo arms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Pancreatitis-Related Emergency Room Visits Not Requiring Hospital Admission Per Participant-Year | From randomization through Week 96 | : The total number of emergency room visits attributed to pancreatitis, comprising visits for pancreatic pain, for episodes of acute pancreatitis, or for pancreatitis-related complications, that did not result in hospital admission, divided by the total participant-years of follow-up. Reported as events per participant-year; higher values indicate more frequent visits. |
| Rate of Pancreatitis-Related Hospital Admissions Per Participant-Year | From randomization through Week 96 | The total number of hospital admissions attributed to pancreatitis, comprising admissions for pancreatic pain, for episodes of acute pancreatitis, or for pancreatitis-related complications, divided by the total participant-years of follow-up. Reported as events per participant-year; higher values indicate more frequent admissions. |
| Number of Participants With at Least One Documented Episode of Acute Pancreatitis | From randomization through Week 96 | An episode of acute pancreatitis is documented by amylase or lipase elevation of two times or more the upper limit of normal, by findings of pancreatic inflammation on cross-sectional imaging, or by clinical diagnosis alone. Episodes are counted whether or not they result in an emergency room visit or hospital admission. A participant is counted once if one or more such episodes occur. |
| Mean Change From Baseline in PROMIS Global Health Global Physical Health T-Score | Baseline (Week 0), Week 48, and Week 96 | The Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health short form is self-completed by the participant. Global Physical Health raw scores are converted to a T-score calibrated so that the United States general population has a mean of 50 and a standard deviation of 10. Higher scores indicate better physical health. |
| Mean Change From Baseline in PROMIS Global Health Global Mental Health T-Score | Baseline (Week 0), Week 48, and Week 96 | The Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health short form is self-completed by the participant. Global Mental Health raw scores are converted to a T-score calibrated so that the United States general population has a mean of 50 and a standard deviation of 10. Higher scores indicate better mental health. |
| Mean Change From Baseline in Comprehensive Pain Assessment Tool Short Form (COMPAT-SF) Total Score | Baseline (Week 0), Week 48, and Week 96 | The Comprehensive Pain Assessment Tool Short Form is a pancreatitis-specific multidimensional pain instrument self-completed by the participant. Higher scores indicate greater pain burden. |
| Mean Change From Baseline in Brief Pain Inventory Pain Severity Score | Baseline (Week 0), Week 48, and Week 96 | The Brief Pain Inventory is self-completed by the participant. The four pain severity items are each scored from 0, no pain, to 10, pain as bad as you can imagine, and are averaged to produce a severity score ranging from 0 to 10. Higher scores indicate greater pain severity. |
| Mean Change From Baseline in PANQOLI Role Function Subscale Score | Baseline (Week 0), Week 48, and Week 96 | The role function subscale of the Pancreatitis Quality of Life Instrument (PANQOLI) is self-completed by the participant. |
| Mean Change From Baseline in Opioid Use Measured in Morphine Milligram Equivalents | The 30 days preceding Baseline (Week 0), Week 48, and Week 96 | Opioid dispensing records are obtained from the Prescription Drug Monitoring Program with participant consent and are complemented by participant-reported intake. Total opioid consumption over the 30 days preceding each assessment is converted to morphine milligram equivalents using established conversion factors. Higher values indicate greater opioid use. |
| Number of Participants With a New Diagnosis of Pancreatic Endocrine Dysfunction | Baseline (Week 0), Week 48, and Week 96 | Endocrine status is determined by hemoglobin A1c and by fasting or random blood glucose, interpreted by the investigator. A new diagnosis is recorded where the investigator determines that endocrine dysfunction is present at an assessment timepoint in a participant who did not have a diagnosis of diabetes at Week 0. A participant is counted once. |
| Number of Participants With a New Diagnosis of Pancreatic Exocrine Dysfunction | Within 2 months after first dose of study drug, at Week 48, and at Week 96 | Exocrine status is determined by fecal elastase measured on a participant-collected stool specimen. A new diagnosis is recorded where the investigator determines that exocrine insufficiency is present at an assessment timepoint in a participant who did not have exocrine insufficiency at the first timepoint. A participant is counted once. |
Contacts
CONTACTVikas Dudeja, MD
CONTACTRimas Nemickas
PRINCIPAL_INVESTIGATORVikas Dudeja, MD
University of Iowa
Outcome results
None listed