Between July, 2007, and June, 2009, 763 patients were screened for the double-blind study, of whom 516 were randomised (). All randomised patients were included in safety analyses, and 513 patients who received treatment were eligible for primary and secondary efficacy analyses. In the first treatment cycle, 85 patients stopped treatment because of protocol-defined dose-stopping events, adverse events, or other reasons (withdrawal from treatment or study, low C-peptide at day 140, insufficient autoantibodies at study entry, pregnancy, or loss to follow-up). In the second treatment cycle at week 26, 18 of 428 patients stopped treatment because of dose-stopping events, adverse events, or other reasons (withdrawal of dosing, insufficient autoantibodies at study entry, or drug supply issue). 1-year follow-up was completed by August, 2010. Many patients who stopped or withdrew from treatment continued to participate; 12 patients withdrew completely from study participation and four patients were lost to follow-up, leaving 497 patients who continued long-term follow-up after 1 year.
Baseline characteristics were well balanced across treatment groups (), but varied by region (webappendix p 7). Most notably, patients in India had higher HbA1C and insulin use, lower AUC of C-peptide (characteristic of later disease stage), and lower frequency of anti-ICA512 antibodies than did those in other regions.
Demographic and clinical characteristics at baseline
HbA1C and insulin use decreased after patients entered the study, and then increased after day 91 (webappendix pp 8–9). Mean changes in HbA1C from baseline were essentially identical in the 14-day full-dose and placebo groups at all times. The 14-day full-dose group had numerically larger decreases in mean insulin use relative to the placebo group, and the difference was maintained at all times (webappendix pp 8–9). Differences between the 14-day full-dose and placebo groups were not significant for the primary and secondary outcomes (). The amount of missing data for these outcomes was generally small. Results were largely unchanged in sensitivity analyses in which alternative methods were used for imputation of missing data.
Primary, secondary, and post-hoc exploratory outcomes at 1 year
AUC of C-peptide was analysed with non-parametric methods because data were not normally distributed. Median change from baseline to 1 year showed less decline in the 14-day full-dose group than in the placebo group (, ). The shift between treatment groups is evident from the empirical cumulative distribution curves in the overall population, in which 40% of the 14-day full-dose group had a preservation or increase in AUC of C-peptide relative to baseline compared with 28% of the placebo group ().
Change in AUC of C-peptide from baseline over time and AUC of C-peptide over time
Cumulative distribution of change in AUC of C-peptide from baseline at 1 year
Change in insulin use from baseline did not differ between the 14-day full-dose group and placebo (). However, at any given HbA1C
threshold, a greater percentage of patients in the 14-day full-dose group achieved the threshold at lower insulin dose cutoffs than in the placebo group (, webappendix p 10). This effect was most notable at insulin doses of lower than 0·5 U/kg per day. 5% (19/415) of patients receiving teplizumab were not taking insulin at 1 year compared with no patients in the placebo group (p=0·03), and 15 of these 19 patients had HbA1C
of less than 7%. In the Diabetes Prevention Trial,5
insulin was given to the relatives of patients with type 1 diabetes at a dose of 0·25 U/kg per day because this dose did not increase the occurrence of hypoglycaemia.5
We therefore used the dose of 0·25 U/kg per day as a cutoff in subsequent analyses. The proportion of patients who achieved HbA1C
of less than 7% and insulin use of less than 0·25 U/kg per day was greater in the 14-day full-dose group than in the placebo group for the study overall (, , webappendix p 10) and at each study visit (). A similar effect was seen at HbA1C
of less than 6·5% and insulin use of less than 0·25 U/kg per day (p=0·02).
Proportion of patients with HbA1c <7% by daily insulin dose cutoffs
Proportion of patients who met the post-hoc exploratory outcome of HbA1C <7% and insulin use <0·25 U/kg per day at each study visit
The lower reduction in median AUC of C-peptide in the 14-day full-dose group than in the placebo group was evident in three predefined subgroups (): children aged 8–11 years (, ), the US region (, ), and patients randomised at 6 weeks or fewer after diagnosis (webappendix p 11). Because of violations of normality assumptions, inferen tial comparisons were made with non-parametric methods.
Non-parametric summary statistics and subgroup analysis for change in AUC of C-peptide from baseline to year 1
In the subgroup of the US region, the proportion of patients who achieved an HbA1c of less than 7% at each low dose insulin cutoff was higher in the 14-day full-dose group than in the placebo group (). A similar pattern was seen in children aged 8–11 years and patients randomised at no more than 6 weeks after diagnosis, but data are not shown because sample sizes were small. Furthermore, in the subgroups of children aged 8–11 years, the US region, and patients randomised at 6 weeks or fewer after diagnosis, the proportion of patients who achieved HbA1C of less than 7% and insulin use of less than 0·25 U/kg per day was greater in the 14-day full-dose group than in the placebo group at all timepoints (webappendix pp 12–14).
In the safety analyses, the proportion of patients who had adverse events (512/516 [99%]) and serious adverse events (51/516 [10%]) was similar across the four study groups (). The proportion of patients with infection did not differ between the four treatment groups (). Although the study population had a high occurrence of anti-EBV IgG at baseline (441/513 [86%]), 22 of 415 (5%) patients receiving teplizumab became positive for anti-EBV IgG or IgM during the study compared with seven of 98 (7%) receiving placebo, and only one patient (teplizumab group) had a small transient increase in EBV viral load. 77% (318/415) of patients treated with teplizumab (150/207 [72%] in the 14-day full-dose group, 78/102 [76%] in the 14-day low dose group, and 90/106 [85%] in the 6-day full-dose group) and 13% (13/98) of those receiving placebo developed anti-drug antibodies, defined as a titre of more than 1:100 when samples were obtained at 28 or 56 days.
All serious adverse events, adverse events occurring in 10% or more of patients in any treatment group, and adverse events of special interest
Rash, the most common clinical adverse event in the teplizumab groups, occurred in a higher proportion of patients than in the placebo group (). With median onset at day 6 (IQR 5–11), rash was usually mild to moderate (218/220 [99%]), self-limited in all but one patient, most often maculopapular (132/220 [60%]), and sometimes pruritic 56/220 (25%). Mild cytokine release syndrome was infrequent in the teplizumab groups (22/417 [5%]) and was not recorded in the placebo group (). The safety profile was characterised by transient, small increases in aminotransferases, and mild, transient decreases in the neutrophil and leucocyte concentrations (webappendix pp 15–17). A more profound, but transient drop occurred in the lymphocyte concentration (nadir at day 6), as reported in previous studies12,13
(webappendix pp 15–17). The proportion of patients who were not able to complete all drug doses because of lymphopenia and protocol-defined stopping rules for alanine or aspartate aminotransferase increases, neutropenia, and reduced platelet counts was higher in the teplizumab groups (39/415 [9%]) than in the placebo group (2/98 [2%]).