Multicenter study to assess safety and efficacy of INH-A21, a donor-selected human staphylococcal immunoglobulin, for prevention of nosocomial infections in very low birth weight infants.

BACKGROUND: Prophylactic administration of intravenous immunoglobulin has been inconsistent in reducing the risk of sepsis in very low birth weight (VLBW) infants presumably because of varying titers of organism specific IgG antibodies. INH-A21 is an intravenous immunoglobulin from donors with high titers of antistaphylococcal antibodies. This dose-ranging study explored safety and preliminary activity of INH-A21 for prevention of staphylococcal sepsis in VLBW infants. METHODS: This was a multicenter, double blind, group-sequential study. Infants with birth weights 500-1250 g were randomized to receive up to 4 doses of placebo, 250 mg/kg, 500 mg/kg or 750 mg/kg INH-A21. Safety and frequencies of sepsis were compared across treatment groups. RESULTS: All treatment groups had similar mean gestational age, birth weight, Apgar score and maternal use of antibiotics. Randomizations to 250 mg/kg (N = 94) and 500 mg/kg (N = 96) doses were terminated after interim analyses demonstrated a low probability of finding a difference when compared with placebo. Infants randomized to the INH-A21 750 mg/kg group (N = 157) had fewer episodes of Staphylococcus aureus sepsis [relative risk (RR), 0.37; 95% confidence interval (CI), 0.12-1.12; P = 0.14], candidemia (RR 0.34; 95% CI 0.09-1.22; P = 0.09) and mortality (RR 0.64; 95% CI 0.25-1.61; P = 0.27) when compared with the placebo-treated cohort (N = 158). No dose-related trends were observed for adverse events or morbidities associated with prematurity. CONCLUSIONS: INH-A21 750 mg/kg demonstrated potential to reduce sepsis caused by S. aureus, candidemia and mortality in VLBW infants. Although statistical significance was not reached, based on the magnitude of the estimated differences, the efficacy and safety of INH-A21 750 mg/kg should be evaluated in an adequately powered, well-controlled study.

Multicenter study to determine antibody concentrations and assess the safety of administration of INH-A21, a donor-selected human Staphylococcal immune globulin, in low-birth-weight infants.

Nosocomial or late-onset sepsis is a common complication among premature infants, with a frequency inversely correlated with birth weight. Increased susceptibility to infection is due in part to an immature humoral (antibody-mediated) immune response. This study investigated the pharmacokinetics (PKs) and safety of a donor-selected specific intravenous immune globulin (IVIG) preparation, INH-A21 (Veronate), for prevention of sepsis in premature infants. Thirty-six infants weighing between 500 and 1,250 g during the first postnatal week were eligible to begin a series of up to four intravenous infusions of 500 or 750 mg/kg of body weight INH-A21. Blood samples were analyzed for antibodies against the Ser-Asp dipeptide repeat G (SdrG) and clumping factor A (ClfA) surface proteins of staphylococci. Sparse sampling and population PK analyses were performed to derive PK parameters. Following administration of the 500- and 750-mg/kg doses, the estimated average steady-state levels of anti-ClfA were 6.1 U/ml and 9.2 U/ml, respectively, and those of anti-SdrG were 5.2 U/ml and 7.7 U/ml, respectively. The elimination half-lives for anti-ClfA and anti-SdrG were 719 h and 701 h, respectively, and the clearances were 0.18 ml/h and 0.21 ml/h, respectively. In the final model, the values of the PK parameters were independent of gestational age. Both doses of INH-A21 were well tolerated, and the safety profile was similar to those of other IVIG preparations. These results suggest that a shorter dosing interval should be utilized between the first and second doses to achieve and maintain higher titers of anti-ClfA and anti-SdrG antibodies. Further studies examining INH-A21 for the prevention of late-onset sepsis in infants within the weight range studied are warranted.