Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes
Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte gl...
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| Published in | The Journal of clinical investigation Vol. 125; no. 1; pp. 448 - 455 |
|---|---|
| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Society for Clinical Investigation
01.01.2015
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0021-9738 1558-8238 1558-8238 |
| DOI | 10.1172/JCI78492 |
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| Abstract | Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and <2 years).
A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/m²; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years.
Combination ATG/G-CSF treatment tended to preserve β cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001-0.552, P = 0.050). A1c was lower in ATG/G-CSF-treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs.
Patients with established T1D may benefit from combination immunotherapy approaches to preserve β cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease.
Clinicaltrials.gov NCT01106157.
The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi. |
|---|---|
| AbstractList | Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and <2 years).BACKGROUNDPrevious efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and <2 years).A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/m²; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years.METHODSA randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/m²; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years.Combination ATG/G-CSF treatment tended to preserve β cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001-0.552, P = 0.050). A1c was lower in ATG/G-CSF-treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs.RESULTSCombination ATG/G-CSF treatment tended to preserve β cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001-0.552, P = 0.050). A1c was lower in ATG/G-CSF-treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs.Patients with established T1D may benefit from combination immunotherapy approaches to preserve β cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease.CONCLUSIONSPatients with established T1D may benefit from combination immunotherapy approaches to preserve β cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease.Clinicaltrials.gov NCT01106157.TRIAL REGISTRATIONClinicaltrials.gov NCT01106157.The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi.FUNDINGThe Leona M. and Harry B. Helmsley Charitable Trust and Sanofi. TRIAL REGISTRATION. Clinicaltrials.gov NCT01106157. BACKGROUND. Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and <2 years). METHODS. A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/m 2 ; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years. RESULTS. Combination ATG/G-CSF treatment tended to preserve β cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001–0.552, P = 0.050). A1c was lower in ATG/G-CSF–treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs. CONCLUSIONS. Patients with established T1D may benefit from combination immunotherapy approaches to preserve β cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease. TRIAL REGISTRATION. Clinicaltrials.gov NCT01106157. FUNDING. The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi. BACKGROUND. Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and <2 years). METHODS. A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/[m.sup.2]; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years. RESULTS. Combination ATG/G-CSF treatment tended to preserve β cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001-0.552, P = 0.050). A1c was lower in ATG/G-CSF-treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs. CONCLUSIONS. Patients with established T1D may benefit from combination immunotherapy approaches to preserve β cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease. TRIAL REGISTRATION. Clinicaltrials.gov NCT01106157. FUNDING. The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi. Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and <2 years). A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/m²; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years. Combination ATG/G-CSF treatment tended to preserve β cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001-0.552, P = 0.050). A1c was lower in ATG/G-CSF-treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs. Patients with established T1D may benefit from combination immunotherapy approaches to preserve β cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease. Clinicaltrials.gov NCT01106157. The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi. A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received anti-thymocyte globulin (ATG) (2.5 mg/kg intravenously) followed by pegylated granulocyte CSF (G-CSF) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test. At baseline, the age was 24.6 plus or minus 10 years; mean BMI was 25.4 plus or minus 5.2 kg/m super( 2); mean A1c was 6.5% plus or minus 1.1%; insulin use was 0.31 plus or minus 0.22 units/kg/d; and length of diagnosis was 1 plus or minus 0.5 years. Combination ATG/G-CSF treatment tended to preserve beta cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min. A1c was lower in ATG/G-CSF-treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs. |
| Audience | Academic |
| Author | Brusko, Todd M. Schatz, Desmond A. Mathews, Clayton E. Atkinson, Mark A. Michels, Aaron W. Rosenthal, Stephen M. Wasserfall, Clive H. Gitelman, Stephen E. Haller, Michael J. Zou, Baiming Shuster, Jonathan J. Hulme, Maigan A. Gottlieb, Peter A. |
| AuthorAffiliation | 1 Department of Pediatrics, Division of Endocrinology, University of Florida, Gainesville, Florida, USA 3 Department of Pediatrics and Medicine, Division of Endocrinology, University of Colorado, Denver, Colorado, USA 4 Department of Biostatistics and 2 Department of Pediatrics, Division of Endocrinology, UCSF, San Francisco, California, USA 5 Department of Pathology, University of Florida, Gainesville, Florida, USA |
| AuthorAffiliation_xml | – name: 5 Department of Pathology, University of Florida, Gainesville, Florida, USA – name: 2 Department of Pediatrics, Division of Endocrinology, UCSF, San Francisco, California, USA – name: 4 Department of Biostatistics and – name: 1 Department of Pediatrics, Division of Endocrinology, University of Florida, Gainesville, Florida, USA – name: 3 Department of Pediatrics and Medicine, Division of Endocrinology, University of Colorado, Denver, Colorado, USA |
| Author_xml | – sequence: 1 givenname: Michael J. surname: Haller fullname: Haller, Michael J. – sequence: 2 givenname: Stephen E. surname: Gitelman fullname: Gitelman, Stephen E. – sequence: 3 givenname: Peter A. surname: Gottlieb fullname: Gottlieb, Peter A. – sequence: 4 givenname: Aaron W. surname: Michels fullname: Michels, Aaron W. – sequence: 5 givenname: Stephen M. surname: Rosenthal fullname: Rosenthal, Stephen M. – sequence: 6 givenname: Jonathan J. surname: Shuster fullname: Shuster, Jonathan J. – sequence: 7 givenname: Baiming surname: Zou fullname: Zou, Baiming – sequence: 8 givenname: Todd M. surname: Brusko fullname: Brusko, Todd M. – sequence: 9 givenname: Maigan A. surname: Hulme fullname: Hulme, Maigan A. – sequence: 10 givenname: Clive H. surname: Wasserfall fullname: Wasserfall, Clive H. – sequence: 11 givenname: Clayton E. surname: Mathews fullname: Mathews, Clayton E. – sequence: 12 givenname: Mark A. surname: Atkinson fullname: Atkinson, Mark A. – sequence: 13 givenname: Desmond A. surname: Schatz fullname: Schatz, Desmond A. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25500887$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | COPYRIGHT 2015 American Society for Clinical Investigation Copyright © 2015, American Society for Clinical Investigation 2015 American Society for Clinical Investigation |
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| References | B20 B10 B21 B22 B12 B23 B14 B15 B16 B17 B19 Ludvigsson (B11) 2014; 159 B1 B2 B3 Snarski (B13) 2009; 119 B4 B5 B6 B7 B8 B9 Haller (B18) 2014; 63 Pitman (B24) 1938; 29 24576850 - Immunol Lett. 2014 May-Jun;159(1-2):30-5 24622416 - Lancet Diabetes Endocrinol. 2013 Dec;1(4):306-16 17940453 - Curr Opin Endocrinol Diabetes Obes. 2007 Aug;14(4):283-7 15919798 - Diabetes. 2005 Jun;54(6):1763-9 3045545 - N Engl J Med. 1988 Sep 8;319(10):599-604 22697286 - J Diabetes. 2012 Dec;4(4):359-61 19147574 - Cancer Res. 2009 Jan 15;69(2):599-608 24296850 - Diabetes Care. 2014 Apr;37(4):1069-75 23086558 - Diabetologia. 2013 Feb;56(2):391-400 20581881 - Bone Marrow Transplant. 2011 Apr;46(4):562-6 23890997 - Lancet. 2014 Jan 4;383(9911):69-82 20067954 - Diabetes Care. 2010 Apr;33(4):826-32 17426276 - JAMA. 2007 Apr 11;297(14):1568-76 24026563 - Diabetes Care. 2014 Feb;37(2):453-9 25500880 - J Clin Invest. 2015 Jan;125(1):94-6 19694226 - Pol Arch Med Wewn. 2009 Jun;119(6):422-6 19628781 - Diabetes. 2009 Oct;58(10):2277-84 22721971 - Diabetes. 2012 Sep;61(9):2340-8 21714999 - Lancet. 2011 Jul 23;378(9788):319-27 14633822 - Diabetes Care. 2003 Dec;26(12):3326-8 23562090 - Lancet. 2013 Jun 1;381(9881):1905-15 22296077 - N Engl J Med. 2012 Feb 2;366(5):433-42 19366777 - JAMA. 2009 Apr 15;301(15):1573-9 |
| References_xml | – ident: B23 doi: 10.1158/0008-5472.CAN-08-2361 – ident: B15 doi: 10.1111/j.1753-0407.2012.00214.x – volume: 63 start-page: A428 year: 2014 ident: B18 publication-title: Diabetes. – ident: B7 doi: 10.2337/dc13-0604 – ident: B20 doi: 10.2337/dc09-1349 – ident: B16 doi: 10.1001/jama.2009.470 – volume: 159 start-page: 30 year: 2014 ident: B11 publication-title: Immunol Lett. doi: 10.1016/j.imlet.2014.02.006 – ident: B14 doi: 10.1038/bmt.2010.147 – ident: B4 doi: 10.1056/NEJMoa1107096 – ident: B21 doi: 10.2337/db12-0049 – ident: B10 doi: 10.1097/MED.0b013e32825a673b – ident: B17 doi: 10.2337/db09-0557 – ident: B19 doi: 10.1016/S2213-8587(13)70065-2 – ident: B2 doi: 10.1056/NEJM198809083191002 – ident: B12 doi: 10.1001/jama.297.14.1568 – ident: B8 doi: 10.2337/dc13-0626 – ident: B1 doi: 10.1016/S0140-6736(13)60591-7 – volume: 119 start-page: 422 year: 2009 ident: B13 publication-title: Pol Arch Med Wewn. doi: 10.20452/pamw.725 – ident: B3 doi: 10.2337/diabetes.54.6.1763 – ident: B5 doi: 10.1016/S0140-6736(11)60895-7 – ident: B9 doi: 10.2337/diacare.26.12.3326 – volume: 29 start-page: 322 year: 1938 ident: B24 publication-title: Biometrika. – ident: B22 doi: 10.1007/s00125-012-2753-4 – ident: B6 doi: 10.1016/S0140-6736(13)60023-9 – reference: 19147574 - Cancer Res. 2009 Jan 15;69(2):599-608 – reference: 21714999 - Lancet. 2011 Jul 23;378(9788):319-27 – reference: 23086558 - Diabetologia. 2013 Feb;56(2):391-400 – reference: 19628781 - Diabetes. 2009 Oct;58(10):2277-84 – reference: 3045545 - N Engl J Med. 1988 Sep 8;319(10):599-604 – reference: 24622416 - Lancet Diabetes Endocrinol. 2013 Dec;1(4):306-16 – reference: 19366777 - JAMA. 2009 Apr 15;301(15):1573-9 – reference: 15919798 - Diabetes. 2005 Jun;54(6):1763-9 – reference: 25500880 - J Clin Invest. 2015 Jan;125(1):94-6 – reference: 23890997 - Lancet. 2014 Jan 4;383(9911):69-82 – reference: 20067954 - Diabetes Care. 2010 Apr;33(4):826-32 – reference: 20581881 - Bone Marrow Transplant. 2011 Apr;46(4):562-6 – reference: 14633822 - Diabetes Care. 2003 Dec;26(12):3326-8 – reference: 24296850 - Diabetes Care. 2014 Apr;37(4):1069-75 – reference: 22697286 - J Diabetes. 2012 Dec;4(4):359-61 – reference: 17426276 - JAMA. 2007 Apr 11;297(14):1568-76 – reference: 17940453 - Curr Opin Endocrinol Diabetes Obes. 2007 Aug;14(4):283-7 – reference: 24576850 - Immunol Lett. 2014 May-Jun;159(1-2):30-5 – reference: 22721971 - Diabetes. 2012 Sep;61(9):2340-8 – reference: 19694226 - Pol Arch Med Wewn. 2009 Jun;119(6):422-6 – reference: 22296077 - N Engl J Med. 2012 Feb 2;366(5):433-42 – reference: 23562090 - Lancet. 2013 Jun 1;381(9881):1905-15 – reference: 24026563 - Diabetes Care. 2014 Feb;37(2):453-9 |
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| Snippet | Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents... BACKGROUND. Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory... TRIAL REGISTRATION. Clinicaltrials.gov NCT01106157. A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received anti-thymocyte globulin (ATG) (2.5 mg/kg... BACKGROUND. Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory... |
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| SubjectTerms | Adolescent Adult Antilymphocyte Serum - therapeutic use C-Peptide - blood Care and treatment Child Clinical Medicine Diabetes Mellitus, Type 1 - blood Diabetes Mellitus, Type 1 - drug therapy Drug Combinations Female Glycated Hemoglobin A - metabolism Granulocyte Colony-Stimulating Factor - therapeutic use Health aspects Humans Hypoglycemic Agents - therapeutic use Immunotherapy Insulin - therapeutic use Insulin-Secreting Cells - physiology Male Middle Aged Pancreatic beta cells Physiological aspects Polyethylene Glycols - therapeutic use Single-Blind Method Treatment Outcome Type 1 diabetes Young Adult |
| Title | Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes |
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