Anti-inflammatory Therapy to Improve Outcomes After TPIAT

NCT02713997 | Completed Phase 4 Results DMC

• 2 other identifiers: PEDS-2016-22934R01DK109914
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Pancreatitis, Chronic; Diabetes; Transplant

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (22)

• ACRmax

  1 year

• Maximal Acute Insulin Response to Glucose (AIRmax)

  day 90

• Insulin Independence

  1 year

• Insulin Dose (Unit/Day)

  day 90

• Area Under the Curve (AUC) C-peptide

  day 90, 1 year, 2 years

Study Arms (3)

Standard Care

NO INTERVENTION

Patients in the standard care arm will undergo the usual procedure of TPIAT with no ancillary therapies provided.

etanercept

EXPERIMENTAL

Patients in the etanercept arm will undergo the usual procedure of TPIAT with additional therapy of etanercept.

Drug: etanercept

alpha-1 antitrypsin

EXPERIMENTAL

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

Interventions

etanercept DRUG

50 mg on day 0 SQ; 25 mg subcutaneous (SQ) on days 3, 7, 10, 14, and 21 relative to TPIAT

Also known as: Enbrel

etanercept

Alpha 1-Antitrypsin DRUG

90 mg/kg intravenous infusion on days -1, and +3, 7, 14, 21, and 28 post-transplant

Also known as: Aralast NP

alpha-1 antitrypsin

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Minnesota: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

MeSH Terms

Conditions

Pancreatitis; Bronchiolitis Obliterans Syndrome; Diabetes Mellitus

Interventions

Etanercept; alpha 1-Antitrypsin

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Peptide Fragments; Peptides; Amino Acids, Peptides, and Proteins; Immunoglobulin Constant Regions; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Receptors, Tumor Necrosis Factor; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Glycoproteins; Glycoconjugates; Carbohydrates; Serpins; Acute-Phase Proteins; Alpha-Globulins

Results Point of Contact

• Title: Melena Bellin
• Organization: University of Minnesota

bell0130@umn.edu

612-625-4686

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 29, 2016
• First Posted: March 21, 2016
• Study Start: December 1, 2016
• Primary Completion: July 1, 2023
• Study Completion: May 1, 2025
• Last Updated: June 24, 2025
• Results First Posted: September 26, 2024

Record last verified: 2025-06

Locations

US (1)