Anti-inflammatory Therapy to Improve Outcomes After TPIAT

Study Overview
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Brief Summary
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Patients with severe chronic pancreatitis may be candidates to have their pancreas removed and their islets transplanted into the liver to reduce the risk of diabetes mellitus, a procedure called total pancreatectomy with islet autotransplant (TPIAT). However, over half of patients who have a TPIAT will need to remain on some supplemental insulin life-long after the procedure. We will study therapies that may reduce damage to transplanted islets, and thereby improve long-term outcomes. Two promising anti-inflammatory therapies are available to protect islets from damage at the time of transplant: (1) the Tumor Necrosis Factor (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).

Detailed Description
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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.

Official Title
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Anti-inflammatory Therapy to Improve Outcomes in Patients With Chronic Pancreatitis Undergoing Total Pancreatectomy Islet Autotransplantation

Conditions
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Pancreatitis, Chronic; Diabetes; Transplant

Intervention / Treatment
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* Drug: etanercept
* Drug: Alpha 1-Antitrypsin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18- 68 years. . 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. Able to provide informed consent Exclusion Criteria: 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. 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. Immunoglobulin (IgA) deficiency (serum level <5 mg/dL), which has been associated with hypersensitivity to alpha-1 antitrypsin. 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. Known history of human immunodeficiency virus (HIV) infection, hepatitis B (chronic), or hepatitis C (chronic). History of tuberculosis (TB) (latent or active disease), or positive TB skin test. History of symptomatic fungal lung infection. 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 Any of the following hematologic abnormalities: severe anemia (hgb <10 g/dL), thrombocytopenia (<150/mm3), or neutropenia (<1.0 x109/L). 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. Current or expected use of any other immunosuppressive agent. Known hypersensitivity to etanercept or A1AT. 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). Known coagulopathy, or need for anticoagulant therapy preoperatively (coumadin, enoxaparin), or any history of pulmonary embolism. For females, plans to become pregnant or unwillingness to use birth control for the study duration. Inability to comply with the study protocol. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard Care<br>Patients in the standard care arm will undergo the usual procedure of TPIAT with no ancillary therapies provided. | |
| Experimental: etanercept<br>Patients in the etanercept arm will undergo the usual procedure of TPIAT with additional therapy of etanercept. | Drug: etanercept<br>* 50 mg on day 0 SQ; 25 mg subcutaneous (SQ) on days 3, 7, 10, 14, and 21 relative to TPIAT<br>* Other names: Enbrel;|
| Experimental: alpha-1 antitrypsin<br>Patients in the alpha-1 antitrypsin arm will undergo the usual procedure of TPIAT with additional therapy of alpha-1 antitrypsin (Aralast NP) | Drug: Alpha 1-Antitrypsin<br>* 90 mg/kg intravenous infusion on days -1, and +3, 7, 14, 21, and 28 post-transplant<br>* Other names: Aralast NP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal acute C-peptide response to glucose (ACRmax) | derived from times 0-5 minute C-peptide measures on glucose potentiated arginine stimulation at day 90 post-TPIAT | day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ACRmax | derived from times 0- 5 minute C-peptide values from glucose potentiated arginine | 1 year, 2 year | 
| maximal acute insulin response to glucose (AIRmax) | derived from times 0- 5 minute insulin values from glucose potentiated arginine | day 90, 1 year, 2 year | 
| insulin independence | no insulin use for >14 days | 1 year, 2 year | 
| insulin dose (unit/day) | calculated by average daily insulin dose from 2 weeks of logs | day 90, 1 year, 2 years | 
| area under the curve (AUC) C-peptide | calculated as area under the curve from every 30 minute C-peptide values on mixed meal tolerance test (MMTT) | day 90, 1 year, 2 years | 
| AUC glucose | calculated as area under the curve from every 30 minute glucose values on MMTT | day 90, 1 year, 2 years | 
| absence of severe hypoglycemia (SHE) with A1c <7% | no events meeting American Diabetes Association (ADA criteria for SHE day 28- 365, and day 365- 730 respectively with A1c value of <7% | 1 year, 2 years | 
| Severe Adverse Events |  | cumulative, through 2 year visit |