Bluestone JA, St

Bluestone JA, St. baseline-adjusted geometric mean 2-hour area under the curve (AUC) serum C-peptide following a mixed meal tolerance test at two years. Secondary outcomes include difference between groups in incidence of loss of peak C-peptide to 02 pmol/ml, slope of C-peptide over time, changes in HbA1c and insulin dose, and safety. This trial is registered in (“type”:”clinical-trial”,”attrs”:”text”:”NCT00505375″,”term_id”:”NCT00505375″NCT00505375). Findings Adjusted C-peptide AUC was 59% (95% CI: 61%, 112%) higher at two years with abatacept (0378 pmol/ml) versus placebo (0238 pmol/ml) (p=00029). The difference between groups was present throughout the trial, with an estimated 96 months delay in decline with abatacept. There was lower HbA1c (p 0002) but similar insulin use. There were few, clinically not significant infusion related adverse events and minimal overall adverse events. There was no increase in infections or neutropenia. Interpretation Co-stimulation modulation with abatacept slowed decline of beta cell function over two years. The beneficial effect suggests that T-lymphocyte activation still occurs around the time of clinical diagnosis of T1DM. Yet, despite continued administration of abatacept over 24 months, the decline in beta cell function with abatacept was parallel to that Merimepodib with placebo after six months of treatment, causing us to speculate that T-lymphocyte activation may lessen with time. Further observation will determine whether the beneficial effect continues after cessation of abatacept infusions. Funding National Institutes of Health. + 1) was pre-specified for C-peptide AUC mean and normal plots of the residuals indicated that it was adequate. The C-peptide mean AUC equals the AUC divided by the two-hour interval (i.e. Merimepodib AUC/120). The AUC was computed using the trapezoidal rule from the timed measurements of C-peptide during the MMTT. The time to first stimulated peak C-peptide of less than 02 pmol/ml (a level above which was associated with decreased risk of complications in the DCCT) 3,4 was Merimepodib analyzed using standard survival methods (Cox Model 21 and Kaplan-Meier 22 method). Adverse event grades were analyzed using Wilcoxon Rank Sum Test 23. Mean rate of change of C-peptide mean AUC from 6 to 24 months was estimated using a mixed effects model with both random intercept and slope adjusting for age, gender, baseline C-peptide mean AUC, and treatment assignment. The initial fit included a fixed interaction effect of treatment and time but was removed due to the lack of any statistical evidence of it being other than zero. To assess the treatment effect over the entire time period, a similar mixed model was fitted to the data except time was defined without structure and grouped by six month intervals. A sample size of 108 subjects was planned in order to provide 85% power to detect a 50% increase in geometric mean C-peptide relative to the placebo group using a test at the 005 level (one-sided), with 10% loss to follow-up and a 2:1 allocation to treatment versus control (based on the mean and standard deviation Merimepodib estimates, on the transformed scale, of 0248 and 0179, respectively) 2. Screening of new subjects was closed just after this target sample size was reached. However, subjects who had already begun screening were allowed to proceed. Thus, a total of 112 subjects were randomized. Results Baseline Characteristics The baseline characteristics of the two groups are summarized in Table 1. The only noteworthy imbalances were more males in the placebo group and higher mean HbA1c in the placebo group. Table 1 Baseline Demographic P19 and Laboratory Characteristics of Participants at Entry thead th align=”left” rowspan=”1″ colspan=”1″ /th th align=”center” rowspan=”1″ colspan=”1″ Abatacept br / N=77 /th th align=”center” rowspan=”1″ colspan=”1″ Placebo br / N=35 /th th align=”left” colspan=”3″ valign=”bottom” rowspan=”1″ hr / /th /thead Age- yr?Mean13.9 6.913.7 5.3?Median1214?Range6 C 367 C 34 hr / Male sex- number of patients (%)41 (53.2)25 (71.4) hr / Race* – number of patients (%)?White71 (93.4)32 (91.4) hr / Ethnicity C number of patients (%)?Non-Hispanic67 (87.0)31 (88.6) hr / Number of autoantibodies** – no. of patients (%)?19 (11.7)4 (11.4)?226 (33.8)9 (25.7)?326 (33.8)15 (42.9)?416 (20.8)7 (20.0) hr / Number of days from diagnosis to first infusion87.9 14.183.2 17.8?Range51 C 10838 C 107 hr / Weight (kg)52.6 21.953.0 19.7 hr / Body Mass Index (kg/m2)21.0 4.4820.5 3.9 hr / Mean AUC for C-peptide (pmol/ml)0.743 0.420.745 0.31 hr / Glycated hemoglobin at baseline* (HbA1c -%)6.31 0.806.74 0.94 hr / Total daily insulin dose at baseline* C (U/kg)0.385 0.240.339 0.22 hr / Ketoacidosis at diagnosis C number of patients (%)25 (32.5)8 (22.9) hr / Diabetes associated HLA alleles present* – number of patients (%)?DR3 and DR425 (33.8)16 (48.5)?DR3 only11 (14.9)5 (15.2)?DR4 only30 (40.5)10 (30.3)?Neither8 (10.8)2 ( 6.1) Open in a separate window Unless otherwise indicated statistics displayed are means with standard deviation. *excludes subjects with indicated variable missing (number missing: 1 C race not reported, 2 C glycated Merimepodib hemoglobin, 1 C insulin use, 4 C HLA allele status) **ICA not tested on 16 subjects (considered negative for count) Figure.