Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial

Abstract

Aims/hypothesis: Type 1 diabetes results from a chronic autoimmune process continuing for years after presentation. We tested whether treatment with teplizumab (a Fc receptor non-binding anti-CD3 monoclonal antibody), after the new-onset period, affects the decline in C-peptide production in individuals with type 1 diabetes.

Methods: In a randomised placebo-controlled trial we treated 58 participants with type 1 diabetes for 4-12 months with teplizumab or placebo at four academic centres in the USA. A central randomisation centre used computer generated tables to allocate treatments. Investigators, patients, and caregivers were blinded to group assignment. The primary outcome was a comparison of C-peptide responses to a mixed meal after 1 year. We explored modification of treatment effects in subgroups of patients.

Results: Thirty-four and 29 subjects were randomized to the drug and placebo treated groups, respectively. Thirty-one and 27, respectively, were analysed. Although the primary outcome analysis showed a 21.7% higher C-peptide response in the teplizumab-treated group (0.45 vs 0.371; difference, 0.059 [95% CI 0.006, 0.115] nmol/l) (p = 0.03), when corrected for baseline imbalances in HbA(1c) levels, the C-peptide levels in the teplizumab-treated group were 17.7% higher (0.44 vs 0.378; difference, 0.049 [95% CI 0, 0.108] nmol/l, p = 0.09). A greater proportion of placebo-treated participants lost detectable C-peptide responses at 12 months (p = 0.03). The teplizumab group required less exogenous insulin (p < 0.001) but treatment differences in HbA(1c) levels were not observed. Teplizumab was well tolerated. A subgroup analysis showed that treatment benefits were larger in younger individuals and those with HbA(1c) <6.5% at entry. Clinical responders to teplizumab had an increase in circulating CD8 central memory cells 2 months after enrolment compared with non-responders.

Conclusions/interpretations: This study suggests that deterioration in insulin secretion may be affected by immune therapy with teplizumab after the new-onset period but the magnitude of the effect is less than during the new-onset period. Our studies identify characteristics of patients most likely to respond to this immune therapy.

Trial registration: ClinicalTrials.gov NCT00378508

Funding: This work was supported by grants 2007-502, 2007-1059 and 2006-351 from the JDRF and grants R01 DK057846, P30 DK20495, UL1 RR024139, UL1RR025780, UL1 RR024131 and UL1 RR024134 from the NIH.

Conflict of interest statement

Duality of interest

K. C. Herold and J. A. Bluestone have a patent pending concerning the use of anti-CD3 mAb in combination therapies. J. A. Bluestone has a patent for teplizumab.

Figures

Fig. 1

Enrolment and treatment of study patients. The Figure depicts the flow of patients through the protocol. The reasons for screen failures included insufficient stimulated C-peptide levels, absence of detectable autoantibodies, laboratory abnormalities meeting exclusion criteria, and others. Of the eligible participants, five withdrew before the first dose of study drug. Therefore, 58 participants were included in the endpoint analysis

Fig. 2

C-peptide responses to a MMTT in teplizumab- and placebo-treated participants. (a–c) The mean C-peptide AUC (±95% CI) in participants treated with teplizumab (black bars) and placebo (white bars). The C-peptide AUC at 6 and 12 months adjusting for baseline C-peptide, HbA1c levels and stratum are shown for all participants (a, teplizumab-treated, n=31; placebo-treated, n=27) and for those of diabetes duration 4–8 months (b, teplizumab-treated n=21, placebo-treated n=18) and 9–12 months (c, teplizumab-treated n=10, placebo-treated n=9). (d–f) The percentage change in C-peptide AUC from baseline (±95% CI) in participants treated with teplizumab (circles) and placebo (squares). The percentage change from baseline at months 6 and 12, adjusted for baseline C-peptide, baseline HbA1c level and stratum is shown for all participants (d) and those of diabetes duration 4–8 months (e) and 9–12 months (f) (*p<0.05 teplizumab vs placebo)

Fig. 3

Effect of baseline HbA1c level on response to teplizumab. The AUC from the MMTT (mean±95% CI) at 6 and 12 months after enrolment, adjusted for baseline C-peptide, are shown for participants treated with teplizumab (black bar) and placebo (white bar). (a) HgbA1c <6.5% (teplizumab-treated n=20, placebo-treated n=7) and (b) >6.5% (teplizumab-treated n=10, placebo–treated n=19) (***p<0.01, teplizumab vs placebo)

Fig. 4

Insulin use and HbA1c levels in participants treated with teplizumab and placebo. (a) The total daily insulin use (mean±95% CI), adjusted for baseline and stratum was compared in all participants treated with teplizumab (n=31, circles) and placebo (n=27, squares). There was a significant effect of drug treatment on insulin usage (p=0.014) (*p<0.05, **p<0.02, ***p<0.01 teplizumab vs placebo). (b) The HbA1c levels, adjusted for HbA1c at study entry (mean±95% CI) in all participants are shown. The drug treatment did not have a significant effect on the HbA1c levels (p=0.67, teplizumab vs placebo). To convert values for HgbA1c in % into mmol/mol, subtract 2.15 and multiply by 10.929

Fig. 5

Effect of teplizumab on C-peptide responses and insulin use in young (age 15 years) participants. The C-peptide levels at 6 and 12 months after enrolment, adjusted for baseline C-peptide and HbA1c levels, are shown (mean± 95% CI) for participants treated with teplizumab (black bar) and placebo (white bar). (a) Age 8–14 (teplizumab-treated n=18, placebo–treated n=20) and (b) >15 years (teplizumab-treated n=13, placebo-treated n=7) (*p<0.05, teplizumab vs placebo)

Fig. 6

Changes in CD8+ T cells in teplizumab-treated participants. (a) The number of circulating CD8CM (CD8+CD45RO+CD62L−) T cells (mean±SEM) is shown in teplizumab-treated responders (circles, n=13) and non-responders (squares, n=18) after drug treatment, corrected for the baseline counts. The baseline count of CD8CM cells was (mean±SEM) 0.011±0.002×109 cells/l in non-responders and 0.014±0.003×109 cells/l in responders. The number of cells was increased in responders at month 2 compared with the non-responders (**p=0.018, drug treated responders vs non-responders). (b) The corresponding CD4CM T cell counts (circles, responders; squares, non-responders) are shown. Significant changes in this subpopulation were not detected. (c) FACS plots showing CD8CM T cells before and at month 2 in representative drug- and placebo (Pcbo)-treated participants. The baseline count of CD4CM T cells was 0.12±0.013×109cells/l in non-responders and 0.12±0.017×109 cells/l in responders. The staining for CD45RO and CD62L is shown on gated CD8+ lymphocytes. In the data from a representative drug-treated participant shown, the percentage of CD8CM and EM cells (in the corresponding L quadrants) increased from 6.9% and 16% of CD8+ T cells to 19.1% and 19.4% of CD8+ T cells, respectively, whereas in the placebo-treated patient, the CD8CM and EM cells were 3% and 4.8% before and 2.5% and 3.7% after treatment