Anti-CD3 clinical trials in type 1 diabetes mellitus.

Two humanized, anti-CD3 mAbs with reduced FcR binding, teplizumab and otelixizumab, have been evaluated in over 1500 subjects, ages 7-45, with new and recently diagnosed T1D with a range of intravenous doses (3-48mg) and regimens (6-14 days, single or repeat courses). In general, studies that used adequate dosing demonstrated improvement in stimulated C-peptide responses and reduced need for exogenous insulin for two years and even longer after diagnosis. Drug treatment causes a transient reduction in circulating T cells, but the available data suggest that the mechanism of action may involve induction of regulatory mechanisms. The adverse effects of anti-CD3 treatment are infusion-related and transient. The studies have identified significant differences in efficacy among patient groups suggesting that a key aspect for development of this immune therapy is identification of the demographic, metabolic, and immunologic features that distinguish subjects who are most likely to show beneficial clinical responses.

Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial.

Protégé was a phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study of three intravenous teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes. We sought to determine efficacy and safety of teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response. Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up. Teplizumab (14-day full-dose) reduced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo. In analyses of prespecified and post hoc subsets at entry, U.S. residents, patients with C-peptide mean AUC >0.2 nmol/L, those randomized ≤6 weeks after diagnosis, HbA1c <7.5% (58 mmol/mol), insulin use <0.4 units/kg/day, and 8-17 years of age each had greater teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be reduced versus placebo. Antidrug antibodies developed in some patients, without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. In summary, anti-CD3 therapy reduced C-peptide loss 2 years after diagnosis using a tolerable dose.

Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial.

BACKGROUND: Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve ß-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. METHODS: In this 2-year trial, patients aged 8-35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0·5 U/kg per day and glycated haemoglobin A(1c) (HbA(1C)) of less than 6·5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697. FINDINGS: 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group). INTERPRETATION: Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in ß-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children. FUNDING: MacroGenics, the Juvenile Diabetes Research Foundation, and Eli Lilly.

Detection bias due to the effect of finasteride on prostate volume: a modeling approach for analysis of the Prostate Cancer Prevention Trial.

BACKGROUND: The Prostate Cancer Prevention Trial (PCPT) demonstrated a 24.8% reduction in the 7-year prevalence of prostate cancer among patients treated with finasteride (5 mg daily) compared with that among patients treated with placebo; however, a 25.5% increase in the prevalence of high-Gleason grade tumors was observed, the clinical significance of which is unknown. One hypothesized explanation for this increase is that finasteride reduced prostate volume, leading to detection of more high-grade tumors due to increased sampling density. This possibility was investigated in an observational reanalysis of the PCPT data, with adjustment for sampling density. METHODS: A logistic model for the association of high-grade (Gleason score 7-10) prostate cancer with baseline covariates and/or baseline covariates plus prostate volume and number of cores obtained at biopsy was developed using the placebo group (n = 4775) of the PCPT. This model was then applied to the finasteride group (n = 5123) to compare the predicted and observed numbers of high-grade tumors in that group. In a second approach, odds ratios (ORs) for prostate cancer in the finasteride versus placebo groups calculated from binary and polytomous logistic regression models that contained or excluded covariates for gland volume and number of needle cores were compared. RESULTS: Median prostate volume was 25% lower in the finasteride group (median = 25.1 cm3) than in the placebo group (median = 33.5 cm3). The logistic model developed in the placebo group showed that the likelihood of detection of high-grade prostate cancer decreased as volume increased (for each 10 cm3 increase in prostate volume, OR = 0.81, 95% confidence interval [CI] = 0.74 to 0.90). Based on this model, 239 high-grade prostate cancers were predicted in the finasteride group, whereas 243 were observed, a non-statistically significant difference. Among all participants, the odds ratios for high-grade cancer in the finasteride versus placebo groups decreased from 1.27 (95% CI = 1.05 to 1.54) with adjustment for baseline covariates to 1.03 (95% CI = 0.84 to 1.26) following additional adjustment for gland volume and number of biopsy cores in binary outcome models and from 1.14 (95% CI = 0.94 to 1.38) to 0.88 (95% CI = 0.72 to 1.09) following these adjustments in the polytomous models. CONCLUSIONS: Although analyses using postrandomization data require cautious interpretation, these results suggest that sampling density bias alone could explain the excess of high-grade cancers among the finasteride-assigned participants in the PCPT.

Changes in bone mineral density following discontinuation or continuation of alendronate therapy in glucocorticoid-treated patients: a retrospective, observational study.

OBJECTIVE: To evaluate the effects of discontinuing or continuing alendronate (ALN) therapy on bone mineral density (BMD) after patients on a long-term regimen of glucocorticoids (GCs) completed a 1-year treatment period with ALN. METHODS: Eligible patients were individuals with GC-induced osteoporosis who had received ALN (5 or 10 mg) for 1 year in a prior clinical trial and, at the end of the year, were still taking GCs at an average daily dose of > or =7.5 mg of prednisone or equivalent. Patients were contacted 3-5 years after completion of the prior ALN trial for followup measurements of the lumbar spine BMD and hip BMD, and retrospective information was collected about serious or drug-related adverse experiences and concomitant medication use. Some patients remained on GCs, and some remained on ALN, either alone or in combination with other drugs. The primary response parameter was the percentage change in lumbar spine BMD from the end of year 1 to the followup visit. Change in BMD at the hip was a secondary response parameter. RESULTS: Ninety (49.2%) of the eligible 183 patients participated in the retrospective study. The followup period, which began at the end of year 1 of the original clinical trial, ranged from 3.3 years to 4.6 years. The mean number of days of treatment with ALN was 507. Fifty patients were included in the analysis because they had received supraphysiologic doses of GCs (doses above the lowest tertile of GC use for the study population; that is, higher than approximately 6 mg/day), and they had not taken (defined as <6 months of use) other bone-affecting agents except ALN. Eleven of the 50 patients discontinued taking ALN (duration of use <90 days), 8 took ALN between 90 days and 300 days, and 31 continued to take ALN for >300 days after year 1 of the clinical trial. GC users who discontinued treatment with ALN (<90 days of therapy) had numerically greater decreases in BMD at the lumbar spine, femoral neck, and total hip from the end of year 1 (mean change -5.1%, -9.2%, and -6.6%, respectively), compared with patients who continued to take ALN for >300 days (mean change 0.1%, -0.9%, and 1.8%, respectively). CONCLUSION: Substantial loss of BMD in the lumbar spine and hip was seen in patients who discontinued treatment with ALN but who continued to take >6 mg/day of GCs. However, patients receiving GCs who remained on the ALN regimen appeared to benefit from continued ALN treatment, since BMD was maintained in this latter group.

Therapeutic equivalence of alendronate 35 milligrams once weekly and 5 milligrams daily in the prevention of postmenopausal osteoporosis.

OBJECTIVE: To evaluate the efficacy and safety of alendronate 35 mg once weekly compared with alendronate 5 mg daily in the prevention of osteoporosis. METHODS: We compared the efficacy and safety of treatment with alendronate 35 mg once weekly (n = 362) and alendronate 5 mg daily (n = 361) in a 1-year, double-blind, multicenter study of postmenopausal women (6 months or greater), aged 40-70 years, with lumbar spine and femoral neck bone mineral density T-scores between -2.5 and 1. The primary efficacy end point was the comparability of lumbar spine bone mineral density increases, defined by strict prespecified criteria. RESULTS: Mean increases in lumbar spine bone mineral density at 12 months were equivalent (difference between the alendronate 35-mg once-weekly group and the alendronate 5-mg daily group [90% confidence interval] at month 12 was -0.3% [-0.6, 0.1], well within the prespecified bounds of +/-1.0%). Bone mineral density increases at other skeletal sites and effects on bone turnover were also virtually identical for the two dosing regimens. Both treatment regimens were well tolerated, and the larger weekly unit dose was not associated with an increased frequency of upper gastrointestinal events. CONCLUSION: Alendronate 35 mg once weekly is therapeutically equivalent to alendronate 5 mg daily and provides patients with greater dosing convenience, in addition to the proven efficacy of alendronate and good tolerability.