Pancreatitis, Chronic; Diabetes; Transplant Clinical Trial
Official title:
Anti-inflammatory Therapy to Improve Outcomes in Patients With Chronic Pancreatitis Undergoing Total Pancreatectomy Islet Autotransplantation
| Verified date | August 2023 |
| Source | University of Minnesota |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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).
| Status | Active, not recruiting |
| Enrollment | 44 |
| Est. completion date | May 1, 2025 |
| Est. primary completion date | July 1, 2023 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years to 65 Years |
| Eligibility | 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. |
| Country | Name | City | State |
|---|---|---|---|
| United States | University of Minnesota | Minneapolis | Minnesota |
| Lead Sponsor | Collaborator |
|---|---|
| University of Minnesota | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) |
United States,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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 | ACRmax | derived from times 0- 5 minute C-peptide values from glucose potentiated arginine | 1 year, 2 year | |
| Secondary | 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 | |
| Secondary | insulin independence | no insulin use for >14 days | 1 year, 2 year | |
| Secondary | insulin dose (unit/day) | calculated by average daily insulin dose from 2 weeks of logs | day 90, 1 year, 2 years | |
| Secondary | 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 | |
| Secondary | AUC glucose | calculated as area under the curve from every 30 minute glucose values on MMTT | day 90, 1 year, 2 years | |
| Secondary | 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 | |
| Secondary | Severe Adverse Events | cumulative, through 2 year visit |