Anti-inflammatory Therapy to Improve Outcomes After TPIAT

For patients with severe pancreatitis refractory to medical and endoscopic therapy, total
pancreatectomy (TP) with islet autotransplantation (IAT) may be considered. While 90% of
TPIAT recipients have some function of the transplanted islet graft, only about 1/3rd come
completely off insulin. The long-term goal of the proposed research is to develop new
therapies that will increase the number of patients who are non-diabetic following islet
autotransplant. Such therapies may also benefit recipients of islet allotransplant for type 1
diabetes.

Following islet transplantation, the islets must acutely survive the stress of the procedure,
and then they must engraft in the liver and establish a vascular supply. The greater the
functional islet mass engrafted, the lower the risk of post-operative diabetes. It has been
estimated that more than half of the islet mass may be lost in the early post-transplant
period in islet transplant recipients. Beta cell apoptosis is common during the first month
post-transplant and is upregulated in the presence of inflammatory cytokines such as
TNF-alpha. Thus, a major contributor to islet loss is the inflammatory damage sustained by
the transplanted islets in the early post-transplant period; we propose to directly target
this destructive process.

Two promising anti-inflammatory therapies are available to address this problem: (1) the
TNF-alpha inhibitor etanercept and (2) the serine protease inhibitor alpha-1 antitrypsin.
Both agents are commercially available for clinical trials. Proof-of-principle for etanercept
has been demonstrated in type 1 diabetic allotransplant recipients, in whom a 10 day course
of etanercept early post-transplant significantly improved long-term insulin independence,
due to better survival of the transplanted beta cell mass in the engraftment period. Alpha-1
antitrypsin (A1AT) reduces inflammatory cytokines, protects against cytokine-induced beta
cell apoptosis, and prolongs islet graft survival in mice and intraportal IAT non-human
primates.

This initial 3-arm drug-treatment clinical trial will investigate the use of Etanercept and
A1AT to improve IAT function at 90 days and 1 and 2 years post-TPIAT compared to standard
care. Forty-five patients undergoing TPIAT will be randomized 1:1:1 to receive either: 1)
etanercept (50 mg on day 0; 25 mg on days 3, 7, 10, 14, and 21), 2) alpha-1 antitrypsin (90
mg/kg IV days -1, +3, 7, 14, 21, 28) or 3) standard care. Patients will have mechanistic
assessments drawn in the early post-operative period including inflammatory cytokines and
chemokines and measures of beta cell loss. Metabolic testing will occur at 90, 365, and 730
days post-TPIAT, including mixed meal tolerance testing, IV glucose tolerance testing, and
glucose-potentiated arginine-induced insulin secretion (GPAIS). The latter measures the
maximally stimulated acute C-peptide response (ACRmax) as the best estimate of islet mass and
the primary endpoint (at day 90) for this study. Results will be used to select the most
promising agent for future study in a randomized, blinded multi-center clinical trial.

Inclusion Criteria:

1. Age 18- 68 years. .

2. Scheduled for total pancreatectomy and IAT at University of Minnesota (UM). All
patients who are approved for pancreatectomy and IAT at UM are reviewed by a
multi-disciplinary committee including surgeons, gastroenterologists specializing in
pancreatic disease, a pain specialist, psychologist, and endocrinologist to confirm
the diagnosis of chronic pancreatitis and candidate suitability for surgery.

3. Able to provide informed consent

Exclusion Criteria:

1. Pre-existing diagnosis of diabetes mellitus, fasting blood glucose >115 mg/dl, or
hemoglobin A1c level >6.0% because these are all evidence of inadequate beta-cell
mass.

2. Use of any of the following treatments in the 30 days prior to enrollment: insulin,
metformin, sulfonylureas, glinides, thiazolidinediones, Glucagon Like Peptide (GLP)-1
agonists, dipeptidyl peptidase (DPP-4) inhibitors, or amylin.

3. Immunoglobulin (IgA) deficiency (serum level <5 mg/dL), which has been associated with
hypersensitivity to alpha-1 antitrypsin.

4. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)>2.5 times the upper
limit of normal (ULN). Bilirubin >ULN, unless due to benign diagnosis such as
Gilbert's.

5. Known history of human immunodeficiency virus (HIV) infection, hepatitis B (chronic),
or hepatitis C (chronic).

6. History of tuberculosis (TB) (latent or active disease), or positive TB skin test.

7. History of symptomatic fungal lung infection.

8. History of multiple sclerosis, transverse myelitis, Guillain Barre, or other suspected
demyelinating disease, due to risk of exacerbation of these conditions with use of
etanercept; or prior history of systemic lupus erythematosus

9. Any of the following hematologic abnormalities: severe anemia (hgb <10 g/dL),
thrombocytopenia (<150/mm3), or neutropenia (<1.0 x109/L).

10. Current use or expected use of oral or injected corticosteroids, or any mediation
likely to affect glucose tolerance. However, use of hydrocortisone for physiologic
replacement, or use of any topical, inhaled, or intranasal glucocorticoid is
permitted.

11. Current or expected use of any other immunosuppressive agent.

12. Known hypersensitivity to etanercept or A1AT.

13. Any condition that is likely, in the opinion of the patient's medical providers, to
necessitate use of TNF alpha therapeutically in the future (such as psoriatic
arthritis).

14. Known coagulopathy, or need for anticoagulant therapy preoperatively (coumadin,
enoxaparin), or any history of pulmonary embolism.

15. For females, plans to become pregnant or unwillingness to use birth control for the
study duration.

16. Inability to comply with the study protocol.

17. Untreated psychiatric illness that may interfere with ability to give informed
consent, or other developmental delay or neurocognitive disorder that impairs with a
patient's ability to consent on their own behalf.

18. Any other medical condition that, in the opinion of the investigator, may interfere
with the patient's ability to successfully and safely complete the trial.