Hydroxychloroquine and Metabolic Outcomes in Patients Undergoing TPAIT

A compelling level of evidence exists on the effects of the innate immunity-driven
inflammation on the decline of functional beta cell mass in the autologous transplant
setting. The investigators hypothesize that HCQ administration during the peri-transplant
period will preserve islet mass and improve islet cell function in TPAIT by reducing
inflammation. The investigators specifically aim to demonstrate a higher stimulated C-peptide
level as well as greater glucose control in response to mixed meal tolerance testing (MMTT)
at 6 and 12 months following TPAIT in patients treated with HCQ compared to placebo. A better
response in the HCQ arm suggests improved islet survival and metabolic performance,
potentially facilitating higher rates of insulin independence.

HCQ administration:

Arm 1 (n=5): Subjects will receive a pre-transplant HCQ 200 mg daily dose 30 days prior TPAIT
followed by HCQ use for an additional 3 months post-surgery.

Arm 2 (n=5) subjects will receive placebo treatment following the same schedule as in Arm 1.

Exploratory mechanistic studies:

All subjects will undergo a MMTT to assess islet cell function at 6 and 12 months following
TPAIT (in addition to MMTT pre-surgery performed as standard of care, and whose results will
be used for pre-randomization in this pilot). Baseline metabolic tests obtained too early
after surgery may not be indicative of islet function, due to insulin supporting therapy
administered for several weeks after transplantation. Also, compelling data indicate that
stabilization of islet function may require up to 1 year to occur. Blood glucose and
C-peptide serum levels will be measured in peripheral blood samples immediately prior and
subsequent to MMTT. The research coordinator will contact the subjects at 3, 6 and 12 months
for interview on the course of follow up and will assist in scheduling the 6 and 12-month
appointments for MMTT.

Mitochondrial Function and Metabolic Outcomes in TPAIT:

Mitochondrial efficiency is important in the setting of TPAIT, where increase in metabolic
demand and decrease in oxygenation have been established. The investigators will assess
mitochondrial efficiency by measuring rates of mitochondrial respiration and glycolysis.
These measures will be obtained on islets procured for donation and after islet isolation.
Small amounts of digest left after islet isolation, that would normally be discarded, will be
used for this portion of the study. The islets from the digest will be collected and will
undergo extracellular efflux analysis through the Seahorse XF analyzer for mitochondrial
function assessment. Commercially available normal human islet cells for experiments will be
used as control. Controls will be compared simultaneously with islets isolated from study
subjects.

Genome-wide Gene Expression in TPAIT Patients:

On the genomic level, several genetic pathways have been implicated in islet cell function
and survival. The genetic profiles of islet cells from CP patients undergoing TPAIT have not
been evaluated yet. The investigators aim to build an RNA-gene sequence database for islet
cells of CP patients undergoing TPAIT, specifically targeting genes previously identified as
key players in islet function. Small amounts of digest from the procedure used for isolating
islets, and what remains in the circuit after the isolation process is complete, that would
normally be discarded, will also be used for islet gene expression assessment.

Inclusion Criteria:

- Clinically confirmed diagnosis of chronic pancreatitis (CP)

- Intractable abdominal pain

- History of failed operation(s) for CP

- Recurrent acute pancreatitis

- HbA1c <8.0%

- Sustained alcohol remission

- Chronic narcotic use

Exclusion Criteria:

- Insulin dependence

- Pancreatic carcinoma

- Pancreatic mass suspicious for carcinoma

- Cirrhosis

- Portal hypertension

- Continued alcohol abuse

- Manufacturer's product label-contraindicated use of HCQ

- History of retinopathy

- Actual weight at enrollment <40 Kg