Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial
Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet f...
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| Published in | The lancet. Diabetes & endocrinology Vol. 1; no. 4; pp. 306 - 316 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Elsevier Ltd
01.12.2013
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results.
For this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12–35 years, and with a peak C-peptide of 0·4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6·5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov, number NCT00515099.
Between Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of −0·195 pmol/mL (95% CI −0·292 to −0·098) and those in the placebo group had a mean change of −0·239 pmol/mL (–0·361 to −0·118) in the placebo group (p=0·591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3–4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases.
Our findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes.
US National Institutes of Health and the Juvenile Diabetes Research Foundation. |
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| AbstractList | Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results.
For this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12-35 years, and with a peak C-peptide of 0.4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6.5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov, number NCT00515099.
Between Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of -0.195 pmol/mL (95% CI -0.292 to -0.098) and those in the placebo group had a mean change of -0.239 pmol/mL (-0.361 to -0.118) in the placebo group (p=0.591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3-4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases.
Our findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes. Summary Background Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results. Methods For this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12–35 years, and with a peak C-peptide of 0·4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6·5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov , number NCT00515099. Findings Between Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of −0·195 pmol/mL (95% CI −0·292 to −0·098) and those in the placebo group had a mean change of −0·239 pmol/mL (–0·361 to −0·118) in the placebo group (p=0·591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3–4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases. Interpretation Our findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes. Funding US National Institutes of Health and the Juvenile Diabetes Research Foundation. Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results. For this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12–35 years, and with a peak C-peptide of 0·4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6·5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov, number NCT00515099. Between Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of −0·195 pmol/mL (95% CI −0·292 to −0·098) and those in the placebo group had a mean change of −0·239 pmol/mL (–0·361 to −0·118) in the placebo group (p=0·591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3–4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases. Our findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes. US National Institutes of Health and the Juvenile Diabetes Research Foundation. Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results.BACKGROUNDType 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results.For this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12-35 years, and with a peak C-peptide of 0.4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6.5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov, number NCT00515099.METHODSFor this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12-35 years, and with a peak C-peptide of 0.4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6.5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov, number NCT00515099.Between Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of -0.195 pmol/mL (95% CI -0.292 to -0.098) and those in the placebo group had a mean change of -0.239 pmol/mL (-0.361 to -0.118) in the placebo group (p=0.591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3-4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases.FINDINGSBetween Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of -0.195 pmol/mL (95% CI -0.292 to -0.098) and those in the placebo group had a mean change of -0.239 pmol/mL (-0.361 to -0.118) in the placebo group (p=0.591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3-4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases.Our findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes.INTERPRETATIONOur findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes. |
| Author | Rigby, Mark R Felner, Eric I Aggarwal, Sudeepta Bluestone, Jeffrey A Willi, Steven M Moran, Antoinette Pinckney, Ashley Moore, Wayne V Ehlers, Mario R Fisher, Lynda K Gottschalk, Michael Keyes-Elstein, Lynette Gitelman, Stephen E Gottlieb, Peter A Phippard, Deborah Sayre, Peter H Ding, Linna |
| Author_xml | – sequence: 1 givenname: Stephen E surname: Gitelman fullname: Gitelman, Stephen E email: sgitelma@peds.ucsf.edu organization: University of California San Francisco, San Francisco, CA, USA – sequence: 2 givenname: Peter A surname: Gottlieb fullname: Gottlieb, Peter A organization: Barbara Davis Center, University of Colorado, Aurora, CO, USA – sequence: 3 givenname: Mark R surname: Rigby fullname: Rigby, Mark R organization: Indiana University and Riley Children's Hospital, Indianapolis, Indianapolis, IN, USA – sequence: 4 givenname: Eric I surname: Felner fullname: Felner, Eric I organization: Emory University, Atlanta, GA, USA – sequence: 5 givenname: Steven M surname: Willi fullname: Willi, Steven M organization: Children's Hospital of Philadelphia, Philadelphia, PA, USA – sequence: 6 givenname: Lynda K surname: Fisher fullname: Fisher, Lynda K organization: Children's Hospital of Los Angeles, Los Angeles, CA, USA – sequence: 7 givenname: Antoinette surname: Moran fullname: Moran, Antoinette organization: University of Minnesota, Minneapolis, MN, USA – sequence: 8 givenname: Michael surname: Gottschalk fullname: Gottschalk, Michael organization: University of California San Diego, San Diego, CA, USA – sequence: 9 givenname: Wayne V surname: Moore fullname: Moore, Wayne V organization: Children's Mercy Hospital, Kansas City, MO, USA – sequence: 10 givenname: Ashley surname: Pinckney fullname: Pinckney, Ashley organization: Rho Federal Systems Division, Chapel Hill, NC, USA – sequence: 11 givenname: Lynette surname: Keyes-Elstein fullname: Keyes-Elstein, Lynette organization: Rho Federal Systems Division, Chapel Hill, NC, USA – sequence: 12 givenname: Sudeepta surname: Aggarwal fullname: Aggarwal, Sudeepta organization: Immune Tolerance Network, Bethesda, MD, USA – sequence: 13 givenname: Deborah surname: Phippard fullname: Phippard, Deborah organization: Immune Tolerance Network, Bethesda, MD, USA – sequence: 14 givenname: Peter H surname: Sayre fullname: Sayre, Peter H organization: Immune Tolerance Network, San Francisco, CA, USA – sequence: 15 givenname: Linna surname: Ding fullname: Ding, Linna organization: National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA – sequence: 16 givenname: Jeffrey A surname: Bluestone fullname: Bluestone, Jeffrey A organization: University of California San Francisco, San Francisco, CA, USA – sequence: 17 givenname: Mario R surname: Ehlers fullname: Ehlers, Mario R organization: Immune Tolerance Network, San Francisco, CA, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24622416$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Contributor | Carchidi, Catherine Rigby, Mark Lungaro, Jenna Sharkey, Maureen Chugha, Preeti Murphy, Laureen Jacobs, Sol Meisner, Stephanie Adi, Saleh Wagner, John Leschyshyn, Janice Wallace, Amy Buchanan, Jeanne Street, Anne Maurer, Heather Moore, Wayne Ahmad, Tariq Gottschalk, Michael Kucheruk, Olena Hashiguchi, Marla Gottlieb, Peter Strickroth, Tracy Hester, Lois Halvorson, Mary Bluestone, Jeff rey Pinckney, Ashley Felner, Eric Michels, Aaron Gitelman, Stephen McFalls, Emily Daniels, Joseph Lund-Fitzgibbon, Peggy Weigel, SueEllen Smith, Jennifer Ehlers, Mario Keyes-Elstein, Lynette Breen, Kathleen Wiseman, Alex Stokes, Alleia Wertz, Marcia Luetjen, Terri Rosenthal, Stephen Langdon, David Moran, Antoinette Lim, Noha Minnock, Pantea Stone, Cheryl Schwartz, Mara Willi, Steven Gibson, Carrie Weiner, Laurie Phippard, Deborah Brown, Milton Voelmle, Mary Flores, Betty Raviele, Nicholas Nathan, Brandon Veri, Maria Aggarwal, Sudeepta Gutin, Ray Meyers, Lisa Plough, Audrey Howell, Michael Sayre, Peter Smallwood, Greg Wesch, Rebecca Fisher, Lynda Debnam, Tracia Morgan, LaSo |
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| Copyright | 2013 Elsevier Ltd Elsevier Ltd Copyright © 2013 Elsevier Ltd. All rights reserved. |
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| Notes | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Undefined-3 START Trial Study Group Immune Tolerance Network, San Francisco, CA, USA—Mario Ehlers, Peter Sayre, Preeti Chugha, Audrey Plough, Maureen Sharkey, Tracy Strickroth. ITN Bethesda: Sudeepta Aggarwal, Michael Howell, Deborah Phippard, Noha Lim, Tracia Debnam; National Institute of Allergy and Infectious Diseases, Bethesda, MA, USA—Linna Ding, Peggy Lund-Fitzgibbon, Maria Veri; Rho Federal Systems Division, Chapel Hill, NC, USA—Ashley Pinckney, Lynette Keyes-Elstein, LaSonia Morgan, Emily McFalls; University of California, San Francisco, CA, USA—Stephen Gitelman, Jeffrey Bluestone, Stephen Rosenthal, Saleh Adi, Marcia Wertz, Rebecca Wesch, Jeanne Buchanan, Kathleen Breen; Barbara Davis Center, Aurora, CO, USA—Peter Gottlieb, Alex Wiseman, Aaron Michels, Ray Gutin, Mary Voelmle, Laurie Weiner, Mara Schwartz, Amy Wallace, Jenna Lungaro, Heather Maurer, Joseph Daniels, Lisa Meyers; Indiana University and Riley Children’s Hospital, Indianapolis, IN, USA—Mark Rigby; Emory University, Atlanta, GA, USA—Eric Felner, Sol Jacobs, Stephanie Meisner, Milton Brown, Nicholas Raviele, Greg Smallwood, Alleia Stokes, Cheryl Stone; Children’s Hospital of Philadelphia, Philadelphia, PA, USA—Steven Willi, Olena Kucheruk, David Langdon, Pantea Minnock, Catherine Carchidi, Laureen Murphy; Children’s Hospital of Los Angeles, Los Angeles, CA, USA—Lynda Fisher, Mary Halvorson; University of Minnesota, Minneapolis, MN, USA—Antoinette Moran, Carrie Gibson, Anne Street, Janice Leschyshyn, Jennifer Smith, Brandon Nathan, John Wagner; University of California–San Diego, CA, USA—Michael Gottschalk, Marla Hashiguchi; Children’s Mercy Hospital, Kansas City, KS, USA—Wayne Moore, SueEllen Weigel, Terri Luetjen, Lois Hester; and Children’s Hospital Oakland, CA, USA—Tariq Ahmad, Betty Flores. SEG was the study chair and wrote the first draft of the paper. Other members of the writing group included MRE, AP, LK-E, and SA. All authors were involved in the conduct of the trial, and the collection and review of the study data. All authors reviewed and commented on versions of the paper. Contributors |
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| PublicationTitle | The lancet. Diabetes & endocrinology |
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| Snippet | Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte... Summary Background Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest... |
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| SubjectTerms | Adolescent Adult Antilymphocyte Serum - therapeutic use Child Diabetes Mellitus, Type 1 - blood Diabetes Mellitus, Type 1 - diagnosis Diabetes Mellitus, Type 1 - drug therapy Double-Blind Method Endocrinology & Metabolism Female Humans Immunologic Factors - therapeutic use Male Other Time Factors Treatment Outcome Young Adult |
| Title | Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial |
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