A randomized controlled pilot trial of etanercept and alpha-1 antitrypsin to improve autologous islet engraftment

Tasneem R. Abdel-Karim; James S Hodges; Timothy L. Pruett; Karthik V Ramanathan; Bernhard J. Hering; Ty B Dunn; Varvara Kirchner; Gregory J. Beilman; Melena D. Bellin

doi:10.1016/j.pan.2022.11.006

A randomized controlled pilot trial of etanercept and alpha-1 antitrypsin to improve autologous islet engraftment

Tasneem R. Abdel-Karim, James S Hodges, Timothy L. Pruett, Karthik V Ramanathan, Bernhard J. Hering, Ty B Dunn, Varvara Kirchner, Gregory J. Beilman, Melena D. Bellin

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5 Scopus citations

Abstract

Background: In total pancreatectomy with islet auto-transplantation, successful diabetes outcomes are limited by islet loss from the instant blood mediated inflammatory response. We hypothesized that blockade of the inflammatory response with either etanercept or alpha-1-antitrypsin would improve islet function and insulin independence. Methods: We randomized 43 participants to receive A1AT (90 mg/kg x 6 doses, n = 13), or etanercept (50 mg then 25 mg x 5 doses, n = 14), or standard care (n = 16), aiming to reduce detrimental effects of innate inflammation on early islet survival. Islet graft function was assessed using mixed meal tolerance testing, intravenous glucose tolerance testing, glucose-potentiated arginine-induced insulin secretion studies, HbA1c, and insulin dose 3 months and 1 year post-TPIAT. Results: We observed the most robust acute insulin response (AIRglu) and acute C-peptide response to glucose (ACRglu) at 3 months after TPIAT in the etanercept-treated group (p ≤ 0.02), but no differences in other efficacy measures. The groups did not differ overall at 1 year but when adjusted by sex, there was a trend towards a sex-specific treatment effect in females (AIRglu p = 0.05, ACRglu p = 0.06), with insulin secretion measures highest in A1AT-treated females. Conclusion: Our randomized trial supports a potential role for etanercept in optimizing early islet engraftment but it is unclear whether this benefit is sustained. Further studies are needed to evaluate possible sex-specific responses to either treatment. Clinical trial notation: This study was performed under an Investigational New Drug Application (IND #119828) from the Food and Drug Administration and was registered on clinicaltrials.gov (NCT#02713997).

Original language	English (US)
Pages (from-to)	57-64
Number of pages	8
Journal	Pancreatology
Volume	23
Issue number	1
DOIs	https://doi.org/10.1016/j.pan.2022.11.006
State	Published - Jan 2023

Bibliographical note

Funding Information:
This study was funded by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grant number R01DK109914 (PI Bellin). This research was supported by the National Institutes of Health's National Center for Advancing Translational Sciences , grant UL1TR002494 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health's National Center for Advancing Translational Sciences.

Publisher Copyright:
© 2022 IAP and EPC

Keywords

Chronic pancreatitis
Cytokines
Diabetes
Islet autotransplantation
TPIAT

PubMed: MeSH publication types

Journal Article
Randomized Controlled Trial

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.pan.2022.11.006

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title = "A randomized controlled pilot trial of etanercept and alpha-1 antitrypsin to improve autologous islet engraftment",

abstract = "Background: In total pancreatectomy with islet auto-transplantation, successful diabetes outcomes are limited by islet loss from the instant blood mediated inflammatory response. We hypothesized that blockade of the inflammatory response with either etanercept or alpha-1-antitrypsin would improve islet function and insulin independence. Methods: We randomized 43 participants to receive A1AT (90 mg/kg x 6 doses, n = 13), or etanercept (50 mg then 25 mg x 5 doses, n = 14), or standard care (n = 16), aiming to reduce detrimental effects of innate inflammation on early islet survival. Islet graft function was assessed using mixed meal tolerance testing, intravenous glucose tolerance testing, glucose-potentiated arginine-induced insulin secretion studies, HbA1c, and insulin dose 3 months and 1 year post-TPIAT. Results: We observed the most robust acute insulin response (AIRglu) and acute C-peptide response to glucose (ACRglu) at 3 months after TPIAT in the etanercept-treated group (p ≤ 0.02), but no differences in other efficacy measures. The groups did not differ overall at 1 year but when adjusted by sex, there was a trend towards a sex-specific treatment effect in females (AIRglu p = 0.05, ACRglu p = 0.06), with insulin secretion measures highest in A1AT-treated females. Conclusion: Our randomized trial supports a potential role for etanercept in optimizing early islet engraftment but it is unclear whether this benefit is sustained. Further studies are needed to evaluate possible sex-specific responses to either treatment. Clinical trial notation: This study was performed under an Investigational New Drug Application (IND #119828) from the Food and Drug Administration and was registered on clinicaltrials.gov (NCT#02713997).",

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author = "Abdel-Karim, {Tasneem R.} and Hodges, {James S} and Pruett, {Timothy L.} and Ramanathan, {Karthik V} and Hering, {Bernhard J.} and Dunn, {Ty B} and Varvara Kirchner and Beilman, {Gregory J.} and Bellin, {Melena D.}",

note = "Funding Information: This study was funded by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grant number R01DK109914 (PI Bellin). This research was supported by the National Institutes of Health's National Center for Advancing Translational Sciences , grant UL1TR002494 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health's National Center for Advancing Translational Sciences. Publisher Copyright: {\textcopyright} 2022 IAP and EPC",

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doi = "10.1016/j.pan.2022.11.006",

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T1 - A randomized controlled pilot trial of etanercept and alpha-1 antitrypsin to improve autologous islet engraftment

AU - Abdel-Karim, Tasneem R.

AU - Hodges, James S

AU - Pruett, Timothy L.

AU - Ramanathan, Karthik V

AU - Hering, Bernhard J.

AU - Dunn, Ty B

AU - Kirchner, Varvara

AU - Beilman, Gregory J.

AU - Bellin, Melena D.

N1 - Funding Information: This study was funded by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grant number R01DK109914 (PI Bellin). This research was supported by the National Institutes of Health's National Center for Advancing Translational Sciences , grant UL1TR002494 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health's National Center for Advancing Translational Sciences. Publisher Copyright: © 2022 IAP and EPC

PY - 2023/1

Y1 - 2023/1

N2 - Background: In total pancreatectomy with islet auto-transplantation, successful diabetes outcomes are limited by islet loss from the instant blood mediated inflammatory response. We hypothesized that blockade of the inflammatory response with either etanercept or alpha-1-antitrypsin would improve islet function and insulin independence. Methods: We randomized 43 participants to receive A1AT (90 mg/kg x 6 doses, n = 13), or etanercept (50 mg then 25 mg x 5 doses, n = 14), or standard care (n = 16), aiming to reduce detrimental effects of innate inflammation on early islet survival. Islet graft function was assessed using mixed meal tolerance testing, intravenous glucose tolerance testing, glucose-potentiated arginine-induced insulin secretion studies, HbA1c, and insulin dose 3 months and 1 year post-TPIAT. Results: We observed the most robust acute insulin response (AIRglu) and acute C-peptide response to glucose (ACRglu) at 3 months after TPIAT in the etanercept-treated group (p ≤ 0.02), but no differences in other efficacy measures. The groups did not differ overall at 1 year but when adjusted by sex, there was a trend towards a sex-specific treatment effect in females (AIRglu p = 0.05, ACRglu p = 0.06), with insulin secretion measures highest in A1AT-treated females. Conclusion: Our randomized trial supports a potential role for etanercept in optimizing early islet engraftment but it is unclear whether this benefit is sustained. Further studies are needed to evaluate possible sex-specific responses to either treatment. Clinical trial notation: This study was performed under an Investigational New Drug Application (IND #119828) from the Food and Drug Administration and was registered on clinicaltrials.gov (NCT#02713997).

AB - Background: In total pancreatectomy with islet auto-transplantation, successful diabetes outcomes are limited by islet loss from the instant blood mediated inflammatory response. We hypothesized that blockade of the inflammatory response with either etanercept or alpha-1-antitrypsin would improve islet function and insulin independence. Methods: We randomized 43 participants to receive A1AT (90 mg/kg x 6 doses, n = 13), or etanercept (50 mg then 25 mg x 5 doses, n = 14), or standard care (n = 16), aiming to reduce detrimental effects of innate inflammation on early islet survival. Islet graft function was assessed using mixed meal tolerance testing, intravenous glucose tolerance testing, glucose-potentiated arginine-induced insulin secretion studies, HbA1c, and insulin dose 3 months and 1 year post-TPIAT. Results: We observed the most robust acute insulin response (AIRglu) and acute C-peptide response to glucose (ACRglu) at 3 months after TPIAT in the etanercept-treated group (p ≤ 0.02), but no differences in other efficacy measures. The groups did not differ overall at 1 year but when adjusted by sex, there was a trend towards a sex-specific treatment effect in females (AIRglu p = 0.05, ACRglu p = 0.06), with insulin secretion measures highest in A1AT-treated females. Conclusion: Our randomized trial supports a potential role for etanercept in optimizing early islet engraftment but it is unclear whether this benefit is sustained. Further studies are needed to evaluate possible sex-specific responses to either treatment. Clinical trial notation: This study was performed under an Investigational New Drug Application (IND #119828) from the Food and Drug Administration and was registered on clinicaltrials.gov (NCT#02713997).

KW - Chronic pancreatitis

KW - Cytokines

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KW - Islet autotransplantation

KW - TPIAT

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A randomized controlled pilot trial of etanercept and alpha-1 antitrypsin to improve autologous islet engraftment

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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