Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial

Mark R. Rigby, Linda A. DiMeglio, Marc S. Rendell, Eric I. Felner, Jean M. Dostou, Stephen E. Gitelman, Chetanbabu M. Patel, Kurt J. Griffin, Eva Tsalikian, Peter A. Gottlieb, Carla J. Greenbaum, Nicole A. Sherry, Wayne V. Moore, Roshanak Monzavi, Steven M. Willi, Philip Raskin, Antoinette Moran, William E. Russell, Ashley Pinckney, Lynette Keyes-ElsteinMichael Howell, Sudeepta Aggarwal, Noha Lim, Deborah Phippard, Gerald T. Nepom, James McNamara, Mario R. Ehlers

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Abstract

Background: Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual β cells in patients newly diagnosed with type 1 diabetes. Methods: The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458. Findings: Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0·015 nmol/L (95% CI -0·080 to 0·110) in the alefacept group and decreased by 0·115 nmol/L (-0·278 to 0·047) in the placebo group, and the difference between groups was not significant (p=0·065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0·015 nmol/L [95% CI -0·076 to 0·106] vs decrease of -0·156 nmol/L [-0·305 to -0·006]; p=0·019), and daily insulin use (0·48 units per kg per day for placebo vs 0·36 units per kg per day for alefacept; p=0·02) and the rate of hypoglycaemic events (mean of 10·9 events per person per year for alefacept vs 17·3 events for placebo; p1c concentrations at week 52 were not different between treatment groups (p=0·75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred. Interpretation: Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve β-cell function in patients with new-onset type 1 diabetes. Funding: US National Institutes of Health and the Juvenile Diabetes Research Foundation.

Original languageEnglish
Pages (from-to)284-294
Number of pages11
JournalThe Lancet Diabetes and Endocrinology
Volume1
Issue number4
DOIs
StatePublished - 2013

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Type 1 Diabetes Mellitus
Placebos
T-Lymphocytes
C-Peptide
Area Under Curve
Hypoglycemic Agents
Insulin
alefacept
National Institutes of Health (U.S.)
Random Allocation
Autoimmunity
Membrane Proteins
Safety

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine
  • Endocrinology
  • Medicine(all)

Cite this

Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study) : 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial. / Rigby, Mark R.; DiMeglio, Linda A.; Rendell, Marc S.; Felner, Eric I.; Dostou, Jean M.; Gitelman, Stephen E.; Patel, Chetanbabu M.; Griffin, Kurt J.; Tsalikian, Eva; Gottlieb, Peter A.; Greenbaum, Carla J.; Sherry, Nicole A.; Moore, Wayne V.; Monzavi, Roshanak; Willi, Steven M.; Raskin, Philip; Moran, Antoinette; Russell, William E.; Pinckney, Ashley; Keyes-Elstein, Lynette; Howell, Michael; Aggarwal, Sudeepta; Lim, Noha; Phippard, Deborah; Nepom, Gerald T.; McNamara, James; Ehlers, Mario R.

In: The Lancet Diabetes and Endocrinology, Vol. 1, No. 4, 2013, p. 284-294.

Research output: Contribution to journalArticle

Rigby, MR, DiMeglio, LA, Rendell, MS, Felner, EI, Dostou, JM, Gitelman, SE, Patel, CM, Griffin, KJ, Tsalikian, E, Gottlieb, PA, Greenbaum, CJ, Sherry, NA, Moore, WV, Monzavi, R, Willi, SM, Raskin, P, Moran, A, Russell, WE, Pinckney, A, Keyes-Elstein, L, Howell, M, Aggarwal, S, Lim, N, Phippard, D, Nepom, GT, McNamara, J & Ehlers, MR 2013, 'Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial', The Lancet Diabetes and Endocrinology, vol. 1, no. 4, pp. 284-294. https://doi.org/10.1016/S2213-8587(13)70111-6
Rigby, Mark R. ; DiMeglio, Linda A. ; Rendell, Marc S. ; Felner, Eric I. ; Dostou, Jean M. ; Gitelman, Stephen E. ; Patel, Chetanbabu M. ; Griffin, Kurt J. ; Tsalikian, Eva ; Gottlieb, Peter A. ; Greenbaum, Carla J. ; Sherry, Nicole A. ; Moore, Wayne V. ; Monzavi, Roshanak ; Willi, Steven M. ; Raskin, Philip ; Moran, Antoinette ; Russell, William E. ; Pinckney, Ashley ; Keyes-Elstein, Lynette ; Howell, Michael ; Aggarwal, Sudeepta ; Lim, Noha ; Phippard, Deborah ; Nepom, Gerald T. ; McNamara, James ; Ehlers, Mario R. / Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study) : 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial. In: The Lancet Diabetes and Endocrinology. 2013 ; Vol. 1, No. 4. pp. 284-294.
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title = "Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial",
abstract = "Background: Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual β cells in patients newly diagnosed with type 1 diabetes. Methods: The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458. Findings: Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0·015 nmol/L (95{\%} CI -0·080 to 0·110) in the alefacept group and decreased by 0·115 nmol/L (-0·278 to 0·047) in the placebo group, and the difference between groups was not significant (p=0·065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0·015 nmol/L [95{\%} CI -0·076 to 0·106] vs decrease of -0·156 nmol/L [-0·305 to -0·006]; p=0·019), and daily insulin use (0·48 units per kg per day for placebo vs 0·36 units per kg per day for alefacept; p=0·02) and the rate of hypoglycaemic events (mean of 10·9 events per person per year for alefacept vs 17·3 events for placebo; p1c concentrations at week 52 were not different between treatment groups (p=0·75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88{\%}) participants had an adverse event related to study drug versus 15 (94{\%}) participants in the placebo group. In the alefacept group, 14 (42{\%}) participants had grade 3 or 4 adverse events compared with nine (56{\%}) participants in the placebo group; no deaths occurred. Interpretation: Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve β-cell function in patients with new-onset type 1 diabetes. Funding: US National Institutes of Health and the Juvenile Diabetes Research Foundation.",
author = "Rigby, {Mark R.} and DiMeglio, {Linda A.} and Rendell, {Marc S.} and Felner, {Eric I.} and Dostou, {Jean M.} and Gitelman, {Stephen E.} and Patel, {Chetanbabu M.} and Griffin, {Kurt J.} and Eva Tsalikian and Gottlieb, {Peter A.} and Greenbaum, {Carla J.} and Sherry, {Nicole A.} and Moore, {Wayne V.} and Roshanak Monzavi and Willi, {Steven M.} and Philip Raskin and Antoinette Moran and Russell, {William E.} and Ashley Pinckney and Lynette Keyes-Elstein and Michael Howell and Sudeepta Aggarwal and Noha Lim and Deborah Phippard and Nepom, {Gerald T.} and James McNamara and Ehlers, {Mario R.}",
year = "2013",
doi = "10.1016/S2213-8587(13)70111-6",
language = "English",
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pages = "284--294",
journal = "The Lancet Diabetes and Endocrinology",
issn = "2213-8587",
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TY - JOUR

T1 - Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study)

T2 - 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial

AU - Rigby, Mark R.

AU - DiMeglio, Linda A.

AU - Rendell, Marc S.

AU - Felner, Eric I.

AU - Dostou, Jean M.

AU - Gitelman, Stephen E.

AU - Patel, Chetanbabu M.

AU - Griffin, Kurt J.

AU - Tsalikian, Eva

AU - Gottlieb, Peter A.

AU - Greenbaum, Carla J.

AU - Sherry, Nicole A.

AU - Moore, Wayne V.

AU - Monzavi, Roshanak

AU - Willi, Steven M.

AU - Raskin, Philip

AU - Moran, Antoinette

AU - Russell, William E.

AU - Pinckney, Ashley

AU - Keyes-Elstein, Lynette

AU - Howell, Michael

AU - Aggarwal, Sudeepta

AU - Lim, Noha

AU - Phippard, Deborah

AU - Nepom, Gerald T.

AU - McNamara, James

AU - Ehlers, Mario R.

PY - 2013

Y1 - 2013

N2 - Background: Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual β cells in patients newly diagnosed with type 1 diabetes. Methods: The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458. Findings: Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0·015 nmol/L (95% CI -0·080 to 0·110) in the alefacept group and decreased by 0·115 nmol/L (-0·278 to 0·047) in the placebo group, and the difference between groups was not significant (p=0·065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0·015 nmol/L [95% CI -0·076 to 0·106] vs decrease of -0·156 nmol/L [-0·305 to -0·006]; p=0·019), and daily insulin use (0·48 units per kg per day for placebo vs 0·36 units per kg per day for alefacept; p=0·02) and the rate of hypoglycaemic events (mean of 10·9 events per person per year for alefacept vs 17·3 events for placebo; p1c concentrations at week 52 were not different between treatment groups (p=0·75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred. Interpretation: Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve β-cell function in patients with new-onset type 1 diabetes. Funding: US National Institutes of Health and the Juvenile Diabetes Research Foundation.

AB - Background: Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual β cells in patients newly diagnosed with type 1 diabetes. Methods: The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458. Findings: Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0·015 nmol/L (95% CI -0·080 to 0·110) in the alefacept group and decreased by 0·115 nmol/L (-0·278 to 0·047) in the placebo group, and the difference between groups was not significant (p=0·065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0·015 nmol/L [95% CI -0·076 to 0·106] vs decrease of -0·156 nmol/L [-0·305 to -0·006]; p=0·019), and daily insulin use (0·48 units per kg per day for placebo vs 0·36 units per kg per day for alefacept; p=0·02) and the rate of hypoglycaemic events (mean of 10·9 events per person per year for alefacept vs 17·3 events for placebo; p1c concentrations at week 52 were not different between treatment groups (p=0·75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred. Interpretation: Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve β-cell function in patients with new-onset type 1 diabetes. Funding: US National Institutes of Health and the Juvenile Diabetes Research Foundation.

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