Role of a CCK Receptor Antagonist Proglumide in Management of Chronic Pancreatitis

Part-1 open labeled:

At screening, laboratory tests will be performed including: Liver profile, Basic chemistry with renal profile, CBC \& platelets, serum lipase levels, HgbA1C, and CRP. A history and physical exam, and the numeric Pain scale diary will be provided. Subjects will be asked to record their worse pain score on a scale of 0 to 10 for each 24 hours over a seven day period. An average pain score of 5 is required for eligibility. Those meeting enrolment criteria according to lab and clinical criteria will go into the next phase.

Observation phase: Within 14 days ± 3 days, subjects that meet the inclusion criteria will have baseline Pain surveys done (Patient-Reported Outcomes Measurement Information Systems- PROMIS and COMPAT-SF) and keep a diary using the numeric pain scale (NPS) daily to record their maximum pain score for each day. The observation period will be 4 weeks. After completing the observation phase, subjects will come to CRU for the baseline visit. The pain surveys can be given to the subjects at the screening visit or sent to the subjects and completed at their home or with the assistance of the Study Coordinator on the Phone.

Baseline: At the baseline visit in the CRU, Pain diaries will be collected from the observation phase and repeat Pain Surveys will be performed (see outcomes below) and Basic chemistry with renal profile, CBC \& platelets, serum lipase levels, HgbA1C, and CRP will be drawn. A history and physical exam will be performed and one red-top blood tube collected and serum frozen for a biomarker and cytokine panels. A 32-day supply of proglumide (#96) will be dispensed with instructions to administer 400mg po TID. A diary for recording pain, medication diary, recording proglumide consumption and any adverse effects will be dispensed and a follow-up appointment scheduled in 4 weeks ± 4 days.

Follow-up visits: (4 week intervals ± 3 days) Subjects will return at weeks 4, 8, 12 and 16 and bring their daily NPS diaries and medication records and bottles for review and accountability. Pain Surveys will be completed at the visits with the assistance of the study coordinator. Concomitant medications and adverse events will be reviewed. Repeat laboratory tests (same as screening) will be repeated. At weeks 4 and 8 another month's supply of proglumide will be dispensed and new diaries. At week-12 a repeat research blood tube will be collected for the biomarker investigation and for proglumide blood level analysis if needed. At weeks 12 and 16 no medication will be dispensed. The week-16 is the follow-up safety visit off medication. At each follow-up visit, subjects should also be evaluated for signs and symptoms of gallbladder pathology.

Part-2 Randomized placebo controlled pseudo crossover:

The second Part will be a randomized placebo-controlled pseudo-crossover study with N=12 subjects in each arm. Part 2 will not start until all subjects complete Part 1 and there are no safety issues. Note: Subjects that participated in Part 1 may be eligible to participate in Part 2 if the subjects meet all the inclusion criteria. A 90-day washout is required off proglumide.

Screening: Screening for the Part 2 study will be the same as that for Part 1 above. There will be no observation untreated phase in this Part.

Baseline visit: Within 14±3 days after subjects are consented, screened and meet the inclusion criteria, the subject will come to the Clinical research Unit (CRU) at 1 PHC for the baseline visit. Subjects will undergo MRI imaging at this visit or after the subject meets the inclusion criteria within the 14 days. If an abdominal MRI was done within the past 3 months with contrast and imaging of the pancreas, a repeat MRI will not be repeated. At the baseline visit the investigational pharmacist will perform the blinded randomization and either a 45-day supply of proglumide (#135) will be dispensed with instructions to administer 400mg po TID or a 45-day supply of placebo to take po TID. Pain Surveys will be performed (see outcomes below) and basic chemistry with renal profile, CBC \& platelets, serum lipase levels, HgbA1C, and CRP will be drawn. A history and physical exam will be performed and one red-top blood tube collected and serum frozen for a biomarker and cytokine panels. A diary for recording pain, medication diary, recording proglumide consumption and any adverse effects will be dispensed and a follow-up appointment scheduled in 6 weeks ± 4 days.

Follow-up visits: (every 6 weeks ± 3 days); follow up visits will occur at weeks 6, 12, 18, and 24. Pain Surveys will be completed at the visits with the assistance of the study coordinator. Concomitant medications and adverse events will be reviewed. Drug accountability will be done. Repeat laboratory tests will be done: Liver profile, Basic chemistry with renal profile, CBC \& platelets, serum lipase levels, HgbA1C, and CRP. AT week 6 the pharmacy will dispense either proglumide or placebo according to the subject's randomization. Leftover capsules may be redispensed to the subject. AT week-12, all medication will be returned to the pharmacy and a new Rx will be dispensed to all subjects containing active drug, proglumide 400 mg to take po TID. At week-12 another research biomarker / proglumide blood tube will be collected and an MRI (preferably at the same location as Baseline) will be done to evaluate the pancreas. At week 18, another research tube will be collected for research biomarker panel/ proglumide blood analysis and all medication will be returned.

Safety termination visit: Four weeks after completing the treatment phase subjects will return for a safety check. Symptoms will be reviewed; the Numeric pain score assessed; and Laboratory tests will be drawn (Liver profile, Basic chemistry with renal profile, CBC \& platelets, serum lipase levels, HgbA1C, and CRP).