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| ID | Type | Description | Link |
|---|---|---|---|
| R01DK109914 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| etanercept | Drug | 50 mg on day 0 SQ; 25 mg subcutaneous (SQ) on days 3, 7, 10, 14, and 21 relative to TPIAT |
|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| ACRmax | derived from times 0- 5 minute C-peptide values from glucose potentiated arginine | 1 year |
| Maximal Acute Insulin Response to Glucose (AIRmax) | derived from times 0- 5 minute insulin values from glucose potentiated arginine |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Minnesota | Minneapolis | Minnesota | 55455 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Standard Care | Patients in the standard care arm will undergo the usual procedure of TPIAT with no ancillary therapies provided. |
| FG001 | Etanercept | Patients in the etanercept arm will undergo the usual procedure of TPIAT with additional therapy of etanercept. etanercept: 50 mg on day 0 SQ; 25 mg subcutaneous (SQ) on days 3, 7, 10, 14, and 21 relative to TPIAT |
| FG002 | 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) Alpha 1-Antitrypsin: 90 mg/kg intravenous infusion on days -1, and +3, 7, 14, 21, and 28 post-transplant |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Standard Care | Patients in the standard care arm will undergo the usual procedure of TPIAT with no ancillary therapies provided. |
| BG001 | Etanercept | Patients in the etanercept arm will undergo the usual procedure of TPIAT with additional therapy of etanercept. etanercept: 50 mg on day 0 SQ; 25 mg subcutaneous (SQ) on days 3, 7, 10, 14, and 21 relative to TPIAT |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | Posted | Mean | Standard Deviation | ng/mL*min | day 90 |
|
collected over 90 days for all AE and 1 year for SAE
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Standard Care | Patients in the standard care arm will undergo the usual procedure of TPIAT with no ancillary therapies provided. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| abdominal infection | General disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| abdominal infection | General disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Melena Bellin | University of Minnesota | 612-625-4686 | bell0130@umn.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 8, 2017 | Sep 2, 2024 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Nov 25, 2019 | Sep 2, 2024 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D010195 | Pancreatitis |
| D000092122 | Bronchiolitis Obliterans Syndrome |
| D003920 | Diabetes Mellitus |
| ID | Term |
|---|---|
| D010182 | Pancreatic Diseases |
| D004066 | Digestive System Diseases |
| D000092124 | Organizing Pneumonia |
| D001989 | Bronchiolitis Obliterans |
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| ID | Term |
|---|---|
| D000068800 | Etanercept |
| D000515 | alpha 1-Antitrypsin |
| ID | Term |
|---|---|
| D007141 | Immunoglobulin Fc Fragments |
| D007128 | Immunoglobulin Fragments |
| D010446 | Peptide Fragments |
| D010455 | Peptides |
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| Alpha 1-Antitrypsin | Drug | 90 mg/kg intravenous infusion on days -1, and +3, 7, 14, 21, and 28 post-transplant |
|
|
| day 90 |
| Insulin Independence | no insulin use for >14 days | 1 year |
| Insulin Dose (Unit/Day) | calculated by average daily insulin dose from 2 weeks of logs | day 90 |
| ACRmax | derived from times 0- 5 minute C-peptide values from glucose potentiated arginine | 2 year |
| Maximal Acute Insulin Response to Glucose (AIRmax) | derived from times 0- 5 minute insulin values from glucose potentiated arginine | 1 year |
| Maximal Acute Insulin Response to Glucose (AIRmax) | derived from times 0- 5 minute insulin values from glucose potentiated arginine | 2 year |
| Insulin Independence | no insulin use for >14 days | 2 year |
| Insulin Dose (Unit/Day) | calculated by average daily insulin dose from 2 weeks of logs | 1 year |
| Insulin Dose (Unit/Day) | calculated by average daily insulin dose from 2 weeks of logs | 2 year |
| 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) | 90 days |
| 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) | 1 year |
| 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) | 2 year |
| AUC Glucose | calculated as area under the curve from every 30 minute glucose values on MMTT | 90 days |
| AUC Glucose | calculated as area under the curve from every 30 minute glucose values on MMTT | 1 year |
| AUC Glucose | calculated as area under the curve from every 30 minute glucose values on MMTT | 2 year |
| Absence of Severe Hypoglycemia (SHE) With A1c <7% | no events meeting American Diabetes Association (ADA criteria for SHE day 28- 365) | 1 year |
| Absence of Severe Hypoglycemia (SHE) With A1c <7% | no events meeting American Diabetes Association (ADA criteria for SHE day 28- 365) | 2 year |
| BG002 | 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) Alpha 1-Antitrypsin: 90 mg/kg intravenous infusion on days -1, and +3, 7, 14, 21, and 28 post-transplant |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG002 |
| 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) Alpha 1-Antitrypsin: 90 mg/kg intravenous infusion on days -1, and +3, 7, 14, 21, and 28 post-transplant |
|
|
| Secondary | ACRmax | derived from times 0- 5 minute C-peptide values from glucose potentiated arginine | Posted | Mean | Standard Deviation | ng/mL*min | 1 year |
|
|
|
| Secondary | Maximal Acute Insulin Response to Glucose (AIRmax) | derived from times 0- 5 minute insulin values from glucose potentiated arginine | Posted | Mean | Standard Deviation | mU/L*min | day 90 |
|
|
|
| Secondary | Insulin Independence | no insulin use for >14 days | Posted | Count of Participants | Participants | 1 year |
|
|
|
| Secondary | Insulin Dose (Unit/Day) | calculated by average daily insulin dose from 2 weeks of logs | Posted | Mean | Standard Deviation | unit/day | day 90 |
|
|
|
| Secondary | ACRmax | derived from times 0- 5 minute C-peptide values from glucose potentiated arginine | Posted | Mean | Standard Deviation | ng/mL*min | 2 year |
|
|
|
| Secondary | Maximal Acute Insulin Response to Glucose (AIRmax) | derived from times 0- 5 minute insulin values from glucose potentiated arginine | Posted | Mean | Standard Deviation | mU/L*min | 1 year |
|
|
|
| Secondary | Maximal Acute Insulin Response to Glucose (AIRmax) | derived from times 0- 5 minute insulin values from glucose potentiated arginine | Posted | Mean | Standard Deviation | mU/L*min | 2 year |
|
|
|
| Secondary | Insulin Independence | no insulin use for >14 days | Posted | Count of Participants | Participants | 2 year |
|
|
|
| Secondary | Insulin Dose (Unit/Day) | calculated by average daily insulin dose from 2 weeks of logs | Posted | Mean | Standard Deviation | unit/day | 1 year |
|
|
|
| Secondary | Insulin Dose (Unit/Day) | calculated by average daily insulin dose from 2 weeks of logs | Posted | Mean | Standard Deviation | unit/day | 2 year |
|
|
|
| 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) | Posted | Mean | Standard Deviation | ng/mL*min | 90 days |
|
|
|
| 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) | Posted | Mean | Standard Deviation | ng/mL*min | 1 year |
|
|
|
| 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) | Posted | Mean | Standard Deviation | ng/mL*min | 2 year |
|
|
|
| Secondary | AUC Glucose | calculated as area under the curve from every 30 minute glucose values on MMTT | Posted | Mean | Standard Error | mg/dL*min | 90 days |
|
|
|
| Secondary | AUC Glucose | calculated as area under the curve from every 30 minute glucose values on MMTT | Posted | Mean | Standard Error | mg/dL*min | 1 year |
|
|
|
| Secondary | AUC Glucose | calculated as area under the curve from every 30 minute glucose values on MMTT | Posted | Mean | Standard Error | mg/dL*min | 2 year |
|
|
|
| Secondary | Absence of Severe Hypoglycemia (SHE) With A1c <7% | no events meeting American Diabetes Association (ADA criteria for SHE day 28- 365) | Posted | Count of Participants | Participants | 1 year |
|
|
|
| Secondary | Absence of Severe Hypoglycemia (SHE) With A1c <7% | no events meeting American Diabetes Association (ADA criteria for SHE day 28- 365) | Posted | Count of Participants | Participants | 2 year |
|
|
|
| 0 |
| 16 |
| 12 |
| 16 |
| 14 |
| 16 |
| EG001 | Etanercept | Patients in the etanercept arm will undergo the usual procedure of TPIAT with additional therapy of etanercept. etanercept: 50 mg on day 0 SQ; 25 mg subcutaneous (SQ) on days 3, 7, 10, 14, and 21 relative to TPIAT | 0 | 14 | 4 | 14 | 13 | 14 |
| EG002 | 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) Alpha 1-Antitrypsin: 90 mg/kg intravenous infusion on days -1, and +3, 7, 14, 21, and 28 post-transplant | 0 | 13 | 4 | 13 | 13 | 13 |
| abdominal pain | General disorders | Non-systematic Assessment |
|
| diarrhea | General disorders | Non-systematic Assessment |
|
| ALT/AST elevated | General disorders | Non-systematic Assessment |
|
| fever | General disorders | Non-systematic Assessment |
|
| heme: clot or bleed | General disorders | Non-systematic Assessment |
|
| hypotension | General disorders | Non-systematic Assessment |
|
| kidney/bladder issue | General disorders | Non-systematic Assessment |
|
| metabolic and electrolyte abnormalities | General disorders | Non-systematic Assessment |
|
| MSK pain | General disorders | Non-systematic Assessment |
|
| Nausea/Vomiting | General disorders | Non-systematic Assessment |
|
| other GI | General disorders | Non-systematic Assessment |
|
| other infection | General disorders | Non-systematic Assessment |
|
| respiratory disease | General disorders | Non-systematic Assessment |
|
| abdominal pain | General disorders | Non-systematic Assessment |
|
| allergy | General disorders | Non-systematic Assessment |
|
| anemia | General disorders | Non-systematic Assessment |
|
| blurred vision | General disorders | Non-systematic Assessment |
|
| constipation | General disorders | Non-systematic Assessment |
|
| dehydration | General disorders | Non-systematic Assessment |
|
| diarrhea | General disorders | Non-systematic Assessment |
|
| dry mouth | General disorders | Non-systematic Assessment |
|
| edema | General disorders | Non-systematic Assessment |
|
| ALT/AST elevated | General disorders | Non-systematic Assessment |
|
| fever | General disorders | Non-systematic Assessment |
|
| fluid overload | General disorders | Non-systematic Assessment |
|
| heme: clot or bleeding | General disorders | Non-systematic Assessment |
|
| hypotension | General disorders | Non-systematic Assessment |
|
| irregular menses | General disorders | Non-systematic Assessment |
|
| kidney/bladder issue | General disorders | Non-systematic Assessment |
|
| low albumin | General disorders | Non-systematic Assessment |
|
| metabolic/electrolyte abnormality | General disorders | Non-systematic Assessment |
|
| MSK pain | General disorders | Non-systematic Assessment |
|
| Nausea/vomiting | General disorders | Non-systematic Assessment |
|
| Other GI | General disorders | Non-systematic Assessment |
|
| other infection | General disorders | Non-systematic Assessment |
|
| other nervous system | General disorders | Non-systematic Assessment |
|
| post op pain | General disorders | Non-systematic Assessment |
|
| psychiatric | General disorders | Non-systematic Assessment |
|
| respiratory distress | General disorders | Non-systematic Assessment |
|
| sinus tachycardia | General disorders | Non-systematic Assessment |
|
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| D001988 | Bronchiolitis |
| D001991 | Bronchitis |
| D001982 | Bronchial Diseases |
| D012140 | Respiratory Tract Diseases |
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| D006086 | Graft vs Host Disease |
| D007154 | Immune System Diseases |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D000602 |
| Amino Acids, Peptides, and Proteins |
| D007127 | Immunoglobulin Constant Regions |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D018124 | Receptors, Tumor Necrosis Factor |
| D018121 | Receptors, Cytokine |
| D011971 | Receptors, Immunologic |
| D011956 | Receptors, Cell Surface |
| D008565 | Membrane Proteins |
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D015843 | Serpins |
| D000209 | Acute-Phase Proteins |
| D000510 | Alpha-Globulins |