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Background: Eltrombopag (EPAG) is an oral non-peptide thrombopoietinreceptor agonist licensed for the treatment of thrombocytopenia in adults with chronic immune thrombocytopenia (cITP). In children with cITP, there is no agreed-upon standard treatment, and the risks of long-term consequences from current treatments are unacceptable to many families and physicians. Aims: This phase III study was conducted to confirm the efficacy, safety, and tolerability of EPAG in children with cITP. The primary objective was to assess the efficacy of EPAG relative to placebo (PBO) in achieving a consistent platelet response defined as counts ≥50 Gi/L (without rescue) for ≥6 out of 8 weeks between weeks 5 and 12 when administered to pediatric subjects with insufficient response to prior ITP treatment. Methods: Subjects were aged between 1 and <18 years with a confirmed diagnosis of cITP (duration >12 months) and platelet count <30 Gi/L at day 1. Informed consent (and assent as appropriate) was provided. Subjects were stratified as: 12-17 years (Cohort 1), 6-11 years (Cohort 2), and 1-5 years (Cohort 3). Part 1 was a 13-week, double-blind (DB), 2:1 randomization to EPAG or PBO. Subjects could continue stable baseline ITP medications. DB treatment was unblinded at week 13 then subjects began 24 weeks of openlabel (OL) treatment with EPAG. Subjects aged 6-17 years weighing ≥27 kg started treatment at 50 mg, and those weighing <27 kg at 37.5 mg. Subjects aged 1-5 years started treatment at 1.2 mg/kg. Dosing at all ages was reduced for East Asian subjects. Dose was adjusted based on platelet counts to a maximum of 75 mg daily. (Figure presented) Results: 92 subjects were enrolled: 33 to Cohort 1, 39 Cohort 2, and 20 Cohort 3. 63 and 29 subjects were randomized to EPAG and PBO, respectively. 3.4% of subjects on PBO entered the study on ITP treatment compared to 20.6% on EPAG; 6.3% on EPAG had previously undergone splenectomy compared to none on PBO. Dosing regimens: During the DB phase, 63.5% of subjects on EPAG required ≥2 dose adjustments. The median daily dose during the OL phase was 67.7 mg for Cohort 1, 56.9 mg for Cohort 2, and 42.8 mg for Cohort 3. Efficacy: 39.7% of subjects on EPAG met the primary endpoint of consistent response compared to 3.4% on PBO (P<0.001). Response rates were similar across age cohorts at 39% for Cohort 1, 42% Cohort 2, and 36% Cohort 3. 74.6% of subjects on EPAG achieved platelet counts ≥50 Gi/L at least once during the first 12 weeks compared to 20.7% on PBO (P<0.001) (Figure 1). Clinically significant bleeding (World Health Organization grade 2-4) was present at baseline in 28.6% on EPAG and 13.8% on PBO compared to 4.8% at the end of DB phase on EPAG and 6.9% on PBO. In the OL phase, 80.5% of subjects achieved platelet counts ≥50 Gi/L at least once during 24 weeks. Safety: The most common adverse events (AEs) that occurred more frequently on EPAG than PBO included nasopharyngitis, rhinitis, cough, and upper respiratory tract infection. Grade 3/4 AEs occurred in 12.7% of EPAG and 10.3% of PBO subjects. Serious AEs were reported in 8% of subjects on EPAG compared to 14% on PBO. In Part 1, 2 subjects (3%) on EPAG discontinued treatment due to AEs of increased liver transaminases, compared to 1 subject (3%) on PBO who discontinued due to bleeding. Safety in the OL phase was consistent with that in the DB phase. No deaths were reported. Summary and Conclusions: PETIT2 met its primary endpoint, demonstrating that a consistent response to EPAG can be achieved in children with cITP. There were no new safety concerns and few discontinuations due to AEs.
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