Intermediate-dose (0.4 g/kg per Dose) versus standard high-dose (1.0 g/kg per Dose) intravenous immunoglobulin in pediatric primary immune thrombocytopenia: A multicenter randomized non-inferiority trial

Abstract

Abstract Background and Objectives Children presenting to emergency departments with newly diagnosed immune thrombocytopenia (ITP) typically exhibit profound thrombocytopenia (platelet counts <20 × 10⁹/L) and clinically significant mucocutaneous hemorrhage. This critical condition carries a 1–3% risk of intracranial hemorrhage requiring urgent intervention. In China's clinical practice, initiating corticosteroids necessitates diagnostic bone marrow aspiration—a procedure associated with a 2.1–5.4% risk of severe bleeding at such platelet levels, compounded by parental consent rates below 50%. Consequently, intravenous immunoglobulin (IVIG) has emerged as the first-line emergency intervention. However, substantial supply limitations exist: the 2024 National Health Commission report documents a 45% annual IVIG deficit. We investigated whether a reduced initial IVIG dose (0.4 g/kg) could demonstrate non-inferior efficacy to the conventional 1.0 g/kg regimen while optimizing resource utilization. Methods Eligible participants were children aged 2 months to 14 years with newly diagnosed ITP (≤3 months from diagnosis) presenting platelet counts <20 × 10⁹/L. Subjects were randomized 1:1 to receive intravenous immunoglobulin at either 0.4 g/kg per dose (intermediate-dose group) or 1.0 g/kg per dose (standard high-dose group). Treatment discontinuation occurred upon achieving platelet counts ≥50 × 10⁹/L with absence of new hemorrhagic manifestations, though no participant exceeded the maximum cumulative dose of 2 g/kg. The co-primary efficacy endpoints comprised early response defined as platelet count ≥30 × 10⁹/L with ≥2-fold increase from baseline at Day 7, and complete response requiring platelet count ≥100 × 10⁹/L with cessation of bleeding at the same timepoint. Non-inferiority was prespecified with a margin of -10% for the lower boundary of the 95% confidence interval, analyzed per intention-to-treat principles with one-sided α=0.025. Results This prospective trial enrolled 580 children with newly diagnosed immune thrombocytopenia, comprising 320 males and 260 females with a median age of 44 months (range: 1-179 months). Randomization allocated 290 participants each to the experimental group receiving 0.4 g/kg per dose IVIG and the control group receiving 1.0 g/kg per dose IVIG, with balanced baseline characteristics including age, sex distribution, body mass index, pretreatment platelet counts, Buchanan bleeding scores, and antecedent infection rates demonstrating no statistically significant differences (all P> 0.05). Analysis of IVIG administration patterns demonstrated that in the experimental group, 110 children (38.0%) received a single dose, 96 (33.1%) required two doses, and 84 (28.9%) necessitated three or more doses. Conversely, the control group showed 154 children (53.1%) receiving one dose and 136 (46.9%) receiving two doses. The mean cumulative IVIG exposure was significantly lower in the experimental group (0.92 g/kg) compared to the control group (1.29 g/kg) with a substantial difference of 0.37 g/kg (P< 0.001). Efficacy assessments revealed comparable outcomes between groups: early response rates reached 94.5% versus 95.7% (P= 0.619), complete early response rates were 71.8% versus 79.3% (P= 0.126), initial response rates stood at 84.7% versus 85.0% (P= 0.942), and complete initial response rates were 63.9% versus 66.1% (P= 0.698), with all comparisons lacking statistical significance. Notably, the reduced-dose regimen demonstrated superior safety with headache incidence markedly lower in the experimental group (1.4% versus 7.9%, P< 0.001). Importantly, no severe adverse events including intracranial hemorrhage were observed in either treatment arm throughout the study period. Conclusions This multicenter randomized trial establishes that initiating IVIG therapy at 0.4 g/kg per dose provides non-inferior hemostatic efficacy compared to the conventional 1.0 g/kg regimen in Chinese children with ITP. Critically, the reduced-dose protocol achieves a 28.7% decrease in total IVIG consumption (mean difference 0.37 g/kg, P<0.001) while substantially lowering treatment-related morbidity—particularly headache incidence which dropped from 7.9% to 1.4% (P<0.001). These findings offer Class I evidence for optimizing frontline management of pediatric ITP in resource-constrained settings, simultaneously addressing national blood product shortages and reducing familial financial burdens without compromising safety.