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Anti-inflammatory Therapy to Improve Outcomes After TPIAT

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ClinicalTrials.gov Identifier: NCT02713997
Recruitment Status : Recruiting
First Posted : March 21, 2016
Last Update Posted : November 1, 2019
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
University of Minnesota

Tracking Information
First Submitted Date  ICMJE February 29, 2016
First Posted Date  ICMJE March 21, 2016
Last Update Posted Date November 1, 2019
Actual Study Start Date  ICMJE December 2016
Estimated Primary Completion Date January 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 15, 2016)
Maximal acute C-peptide response to glucose (ACRmax) [ Time Frame: day 90 ]
derived from times 0-5 minute C-peptide measures on glucose potentiated arginine stimulation at day 90 post-TPIAT
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02713997 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 22, 2016)
  • ACRmax [ Time Frame: 1 year, 2 year ]
    derived from times 0- 5 minute C-peptide values from glucose potentiated arginine
  • maximal acute insulin response to glucose (AIRmax) [ Time Frame: day 90, 1 year, 2 year ]
    derived from times 0- 5 minute insulin values from glucose potentiated arginine
  • insulin independence [ Time Frame: 1 year, 2 year ]
    no insulin use for >14 days
  • insulin dose (unit/day) [ Time Frame: day 90, 1 year, 2 years ]
    calculated by average daily insulin dose from 2 weeks of logs
  • area under the curve (AUC) C-peptide [ Time Frame: day 90, 1 year, 2 years ]
    calculated as area under the curve from every 30 minute C-peptide values on mixed meal tolerance test (MMTT)
  • AUC glucose [ Time Frame: day 90, 1 year, 2 years ]
    calculated as area under the curve from every 30 minute glucose values on MMTT
  • absence of severe hypoglycemia (SHE) with A1c <7% [ Time Frame: 1 year, 2 years ]
    no events meeting American Diabetes Association (ADA criteria for SHE day 28- 365, and day 365- 730 respectively with A1c value of <7%
  • Severe Adverse Events [ Time Frame: cumulative, through 2 year visit ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 15, 2016)
  • ACRmax [ Time Frame: 1 year, 2 year ]
    derived from times 0- 5 minute C-peptide values from glucose potentiated arginine
  • maximal acute insulin response to glucose (AIRmax) [ Time Frame: day 90, 1 year, 2 year ]
    derived from times 0- 5 minute insulin values from glucose potentiated arginine
  • insulin independence [ Time Frame: 1 year, 2 year ]
    no insulin use for >14 days
  • insulin dose (unit/day) [ Time Frame: day 90, 1 year, 2 years ]
    calculated by average daily insulin dose from 2 weeks of logs
  • area under the curve (AUC) C-peptide [ Time Frame: day 90, 1 year, 2 years ]
    calculated as area under the curve from every 30 minute C-peptide values on MMTT
  • AUC glucose [ Time Frame: day 90, 1 year, 2 years ]
    calculated as area under the curve from every 30 minute glucose values on MMTT
  • abscence of severe hypoglycemia with A1c <7% [ Time Frame: 1 year, 2 years ]
    no events meeting ADA criteria for SHE day 28- 365, and day 365- 730 respectively with A1c value of <7%
  • Severe Adverse Events [ Time Frame: cumulative, through 2 year visit ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Anti-inflammatory Therapy to Improve Outcomes After TPIAT
Official Title  ICMJE Anti-inflammatory Therapy to Improve Outcomes in Patients With Chronic Pancreatitis Undergoing Total Pancreatectomy Islet Autotransplantation
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pancreatitis, Chronic; Diabetes; Transplant
Intervention  ICMJE
  • Drug: etanercept
    50 mg on day 0 SQ; 25 mg subcutaneous (SQ) on days 3, 7, 10, 14, and 21 relative to TPIAT
    Other Name: Enbrel
  • Drug: Alpha 1-Antitrypsin
    90 mg/kg intravenous infusion on days -1, and +3, 7, 14, 21, and 28 post-transplant
    Other Name: Aralast NP
Study Arms  ICMJE
  • No Intervention: Standard Care
    Patients in the standard care arm will undergo the usual procedure of TPIAT with no ancillary therapies provided.
  • Experimental: etanercept
    Patients in the etanercept arm will undergo the usual procedure of TPIAT with additional therapy of etanercept.
    Intervention: Drug: etanercept
  • Experimental: alpha-1 antitrypsin
    Patients in the alpha-1 antitrypsin arm will undergo the usual procedure of TPIAT with additional therapy of alpha-1 antitrypsin (Aralast NP)
    Intervention: Drug: Alpha 1-Antitrypsin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 15, 2016)
45
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2024
Estimated Primary Completion Date January 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02713997
Other Study ID Numbers  ICMJE STUDY00007025
R01DK109914 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Minnesota
Study Sponsor  ICMJE University of Minnesota
Collaborators  ICMJE National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators  ICMJE Not Provided
PRS Account University of Minnesota
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP