Clinical trial NCT02713997: Anti-inflammatory Therapy to Improve Outcomes After TPIAT
Official title: Anti-inflammatory Therapy to Improve Outcomes in Patients With Chronic Pancreatitis Undergoing Total Pancreatectomy Islet Autotransplantation
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Pancreatitis, Chronic; Diabetes; Transplant
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2016-03-21
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Maximal Acute C-peptide Response to Glucose (ACRmax)
timeFrame: day 90
Secondary outcomes:
measure: ACRmax
timeFrame: 1 year
measure: Maximal Acute Insulin Response to Glucose (AIRmax)
timeFrame: day 90
measure: Insulin Independence
timeFrame: 1 year
measure: Insulin Dose (Unit/Day)
timeFrame: day 90
measure: Area Under the Curve (AUC) C-peptide
timeFrame: day 90, 1 year, 2 years
measure: AUC Glucose
timeFrame: day 90, 1 year, 2 years
measure: Absence of Severe Hypoglycemia (SHE) With A1c <7%
timeFrame: 1 year, 2 years
measure: Severe Adverse Events
timeFrame: cumulative, through 2 year visit
measure: ACRmax
timeFrame: 2 year
measure: Maximal Acute Insulin Response to Glucose (AIRmax)
timeFrame: 1 year
measure: Maximal Acute Insulin Response to Glucose (AIRmax)
timeFrame: 2 year
measure: Insulin Independence
timeFrame: 2 year
measure: Insulin Dose (Unit/Day)
timeFrame: 1 year
measure: Insulin Dose (Unit/Day)
timeFrame: 2 year
measure: Area Under the Curve (AUC) C-peptide
timeFrame: 90 days
measure: Area Under the Curve (AUC) C-peptide
timeFrame: 1 year
measure: Area Under the Curve (AUC) C-peptide
timeFrame: 2 year
measure: AUC Glucose
timeFrame: 90 days
measure: AUC Glucose
timeFrame: 1 year
measure: AUC Glucose
timeFrame: 2 year
measure: Absence of Severe Hypoglycemia (SHE) With A1c <7%
timeFrame: 1 year
measure: Absence of Severe Hypoglycemia (SHE) With A1c <7%
timeFrame: 2 year
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
Study officials:
References: