Primary endpoints were pharmacokinetic parameters, including the area under the serum-concentration time curve (AUC0–113 days) and maximum concentration (Cmax). The pharmacokinetic analyses included all subjects for whom the pharmacokinetic parameters could be derived. One subject in the normal group was lost to follow-up after day 14 and was excluded from all other pharmacokinetic analyses. Means for each renal function group were calculated. A nonparametric test for trend analysis was used to assess the effect of decreasing renal function on denosumab disposition. Regression analysis was used to model the relationship between the values of the pharmacokinetic parameters and GFR.
Secondary endpoints included subject incidences of adverse events, clinically significant changes in vital signs, physical examinations, clinical laboratory tests, ECGs, and incidence of anti-denosumab antibodies. Subject incidences of albumin-adjusted serum calcium concentrations <8.0 mg/dL (<2.0 mmol/L), albumin-adjusted serum calcium concentration <7.5 mg/dL (<1.9 mmol/L), serious adverse events of hypocalcemia, and symptomatic adverse events of hypocalcemia were evaluated by renal function group. A post hoc multivariate analysis was conducted to evaluate the association between mean decrease from baseline to nadir serum calcium concentration and baseline characteristics (age, race, sex, CKD stage, serum calcium, serum phosphorus, iPTH, 25-OHD, and 1,25-(OH)2D). Proportions were calculated for subjects with at least a 50% reduction in GFR using the Modification of Diet in Renal Disease (MDRD) equation.23 (link)
Change in sCTX1 concentrations was an exploratory pharmacodynamic endpoint; sCTX1 values below the limit of quantification were set to zero. The Spearman correlation coefficient was calculated for maximum absolute decrease in sCTX1 and (1) baseline iPTH and (2) baseline alkaline phosphatase.
The planned sample size of 46 subjects (12 with normal renal function, 10 each with mild and moderate CKD, 7 with severe CKD, and 7 with kidney failure) was based on practical considerations. After the study protocol was amended to include calcium and vitamin D supplementation, enrollment was increased to include 13 subjects each in the mild CKD and moderate CKD groups, and 8 to 9 subjects each in the severe CKD and kidney failure groups.
Secondary endpoints included subject incidences of adverse events, clinically significant changes in vital signs, physical examinations, clinical laboratory tests, ECGs, and incidence of anti-denosumab antibodies. Subject incidences of albumin-adjusted serum calcium concentrations <8.0 mg/dL (<2.0 mmol/L), albumin-adjusted serum calcium concentration <7.5 mg/dL (<1.9 mmol/L), serious adverse events of hypocalcemia, and symptomatic adverse events of hypocalcemia were evaluated by renal function group. A post hoc multivariate analysis was conducted to evaluate the association between mean decrease from baseline to nadir serum calcium concentration and baseline characteristics (age, race, sex, CKD stage, serum calcium, serum phosphorus, iPTH, 25-OHD, and 1,25-(OH)2D). Proportions were calculated for subjects with at least a 50% reduction in GFR using the Modification of Diet in Renal Disease (MDRD) equation.23 (link)
Change in sCTX1 concentrations was an exploratory pharmacodynamic endpoint; sCTX1 values below the limit of quantification were set to zero. The Spearman correlation coefficient was calculated for maximum absolute decrease in sCTX1 and (1) baseline iPTH and (2) baseline alkaline phosphatase.
The planned sample size of 46 subjects (12 with normal renal function, 10 each with mild and moderate CKD, 7 with severe CKD, and 7 with kidney failure) was based on practical considerations. After the study protocol was amended to include calcium and vitamin D supplementation, enrollment was increased to include 13 subjects each in the mild CKD and moderate CKD groups, and 8 to 9 subjects each in the severe CKD and kidney failure groups.
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