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-Elstein, Michael Howell, Sudeepta Aggarwal, Noha Lim, Deborah Phippard, Gerald T Nepom, James McNamara, Mario R Ehlers, T1DAL Study Team, Mario Ehlers, Carol Soppe, Preeti Chugha, Audrey Plough, Tanya Cope, Judith Evind, Melissa Johnson, Maureen Sharkey, Tracy Strickroth, Sudeepta Aggarwal, Michael Howell, Deborah Phippard, Noha Lim, Tracia Debnam, Winnie Felix, Nancy Skeeter, Peggy Lund-Fitzgibbon, Steve Adah, James McNamara, Ashley Pinckney, Lynette Keyes-Elstein, Mark Rigby, Linda DiMeglio, Carmella Evans-Molina, Stephanie Woerner, Jennifer Terrell, Maria Spall, Vanessa Patrick, Christy Kruse, Ann Nguyen, Peter Gottlieb, Heather Maurer, Carla Greenbaum, Jennifer Bollyky, Srinath Sanda, Marli McCulloch-Olson, Marissa St Marie, Deborah Hefty, S Alice Long, Deborah Hefty, Steven Willi, Olena Kucheruk, David Langdon, Pantea Minnock, Roshanak Monzavi, Mary Halvorson, Jamie Wood, Wayne Moore, Sue Ellen Weigel, Marc Rendell, Kayla Zebrowski, Lisa Kuechenmeister, Michael Ulen, Eric Felner, Stephanie Meisner, Nicholas Raviele, Greg Smallwood, Sol Jacobs, Milton Brown, Cheryl Stone, Nicole Sherry, Sarah Dean, Kurt Griffi, Chetan Patel, Carol Stuehm, Oscar Furet, Stephen Gitelman, Stephen Rosenthal, Saleh Adi, Rebecca Wesch, Christine Torok, Karen Ko, Maria Wertz, Kathleen Breen, Eva Tsalikian, Michael Tansey, Julie Coffey, Sarah Salamati, Joanne Cabbage, Jean Dostou, Gail Fuller, Joseph Largay, Nina Jain, Antoinette Moran, Brandon Nathan, John Wagner, Carrie Gibson, Christine Kwong, Jennifer Smith, Janice Leschyshyn, Philip Raskin, M Lourdes Pruneda, Jamie Arthur Fields, Stefani Fernandez, William Russell, Faith Brendle, 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-Elstein, Michael Howell, Sudeepta Aggarwal, Noha Lim, Deborah Phippard, Gerald T Nepom, James McNamara, Mario R Ehlers, T1DAL Study Team, Mario Ehlers, Carol Soppe, Preeti Chugha, Audrey Plough, Tanya Cope, Judith Evind, Melissa Johnson, Maureen Sharkey, Tracy Strickroth, Sudeepta Aggarwal, Michael Howell, Deborah Phippard, Noha Lim, Tracia Debnam, Winnie Felix, Nancy Skeeter, Peggy Lund-Fitzgibbon, Steve Adah, James McNamara, Ashley Pinckney, Lynette Keyes-Elstein, Mark Rigby, Linda DiMeglio, Carmella Evans-Molina, Stephanie Woerner, Jennifer Terrell, Maria Spall, Vanessa Patrick, Christy Kruse, Ann Nguyen, Peter Gottlieb, Heather Maurer, Carla Greenbaum, Jennifer Bollyky, Srinath Sanda, Marli McCulloch-Olson, Marissa St Marie, Deborah Hefty, S Alice Long, Deborah Hefty, Steven Willi, Olena Kucheruk, David Langdon, Pantea Minnock, Roshanak Monzavi, Mary Halvorson, Jamie Wood, Wayne Moore, Sue Ellen Weigel, Marc Rendell, Kayla Zebrowski, Lisa Kuechenmeister, Michael Ulen, Eric Felner, Stephanie Meisner, Nicholas Raviele, Greg Smallwood, Sol Jacobs, Milton Brown, Cheryl Stone, Nicole Sherry, Sarah Dean, Kurt Griffi, Chetan Patel, Carol Stuehm, Oscar Furet, Stephen Gitelman, Stephen Rosenthal, Saleh Adi, Rebecca Wesch, Christine Torok, Karen Ko, Maria Wertz, Kathleen Breen, Eva Tsalikian, Michael Tansey, Julie Coffey, Sarah Salamati, Joanne Cabbage, Jean Dostou, Gail Fuller, Joseph Largay, Nina Jain, Antoinette Moran, Brandon Nathan, John Wagner, Carrie Gibson, Christine Kwong, Jennifer Smith, Janice Leschyshyn, Philip Raskin, M Lourdes Pruneda, Jamie Arthur Fields, Stefani Fernandez, William Russell, Faith Brendle

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; p<0.0001) was significantly lower at 12 months in the alefacept group than in the placebo group. Mean HbA1c 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.