Phase II, multi-center, 3 part, staggered cohort, open-label and double blind, randomized, placebo controlled study involving 3 age-determined cohorts (Cohort 1: between 12 and 17 years old; Cohort 2: between 6 and 11 years old; Cohort 3: between 1 and 5 years old). Daily dosing with eltrombopag will begin with 5 patients in the oldest age cohort in an open label fashion, and a review of safety, pharmacokinetic and platelet count data will be performed regularly. If no safety concerns are identified after 12 weeks, 18 additional patients will be randomised to placebo or eltrombopag (2:1 randomisation). After 7 weeks of randomized treatment, all patients will receive eltrombopag in an open label fashion. The total duration of treatment with eltrombopag will be 24 weeks. If at the time of the aforementioned 12 week review of the first 5 patients no safety issues are identified, dosing will begin in the next lower age cohort with an initial group of 5 patients. The same procedure will be followed in terms of safety review and subsequent enrolment and randomisation of the additional patients. Initiation of the younger age cohort will take place once data from the previous has been evaluated. Doses will be adjusted according to platelet counts and tolerability. The study will include a review of the safety data by a Data Safety Monitoring Board.
INTRODUCTION: Immune thrombocytopenia (ITP) is a disease characterized by low platelet counts that in children commonly follows an acute self-limiting course but becomes chronic (cITP) in approximately 25% of cases. Quality of life of patients and families is negatively affected by restriction of age-appropriate activities, hemorrhagic manifestations, fear of bleeding, or therapeutic complications (Blanchette 2010). Eltrombopag is an oral thrombopoietin receptor agonist approved for treatment of cITP; PETIT is a 24-week open-label and randomized, placebo-controlled trial of eltrombopag in children with cITP who failed an initial therapy and have platelets <30,000/μL. We report preliminary health-related quality of life (HRQoL) results from PETIT derived from applying the Kids' ITP Tools (KIT; Barnard 2003; Klaassen 2007). METHODS: Initially, 15 patients were enrolled in 3 age cohorts (12–17, 6–11, 1–5 years) and received open-label eltrombopag. Additional patients in each cohort were enrolled into the randomized phase once initial safety and efficacy data became available from the open-label phase. The KIT is scored from 0 (worst) to 100 (best), and was completed by patients in the 2 older cohorts and by parents/guardians of all patients at study entry and treatment weeks 6, 12, and 24. RESULTS: HRQoL data for the 15 open-label patients, 5 from each cohort, are presented. At baseline, 9 (60%) patients had platelets ≤15,000/μL and the incidence of bleeding WHO grades 1–4 and 2–4 was 87% (13/15) and 33% (5/15), respectively. All patients completed 24 weeks of treatment. The mean KIT score at baseline for the 10 patients who were 6–17 years old was 65.7 (range, 42.3–85.6; median, 66.3; parents/guardians mean, 61.9) (Figure 1); the mean baseline score reported by parents on behalf of their children (n=15) was 66.5 (range, 43.0–93.3; median, 64.4). At Week 24, among the 10 patients completing the KIT, 9 had higher scores at Week 24 compared to baseline (mean, 19.6-point improvement; median, 19.2; range, 4.8–37.5). Eight of 9 patients had at least a 5-point increase in score (mean, 21.4-point improvement; median, 20.2; range, 6.7–37.5); an additional patient had a score increase of 4.8 points (80.8 at baseline to 85.6 at Week 24). The remaining patient, who had severely fluctuating platelet counts, had a reduced KIT score compared with baseline by 12.5 points (76.9 at baseline, 64.4 at Week 24). Among parent/guardian assessments, 13/15 reported improved KIT scores at Week 24 (mean, 17.9-point improvement; median, 15.4; range, 2.9–41.1; 1 score was last observation carried forward [LOCF]) (Figure 2). Eleven of 15 had at least a 5-point increase in score (mean, 20.5-point improvement; median, 15.7; range, 11.5–41.1). Two parents scored lower than baseline at 24 weeks: parents of the patient with fluctuating platelets (14.4-point reduction; 64.4 at baseline, 50.0 at Week 24) and of a 4-year-old who failed to respond to eltrombopag (40.4-point reduction; 93.3 at baseline, 52.9 at LOCF [Week 12]). DISCUSSION/CONCLUSIONS: Preliminary data suggest that treatment with eltrombopag is associated with improvements in HRQoL in children with cITP. Final results of PETIT should further the understanding of the potential of eltrombopag treatment to improve HRQoL in pediatric patients and further validate the use of the KIT in assessing treatment outcomes of childhood cITP.
BACKGROUND: The oral thrombopoietin receptor agonist eltrombopag is approved for treatment of adults with chronic immune thrombocytopenia. In the PETIT trial, we aimed to investigate the efficacy and safety of eltrombopag in children with persistent or chronic immune thrombocytopenia.
METHODS: PETIT was a three-part, randomised, multicentre, placebo-controlled study done at 22 centres in the USA, UK, Canada, Spain, France, and the Netherlands. Patients aged 1-17 years with immune thrombocytopenia lasting for 6 months or longer and platelets less than 30 × 10(9) per L who had received at least one previous treatment were enrolled. We enrolled patients into three cohorts consisting of patients aged 12-17, 6-11, and 1-5 years. We established patients' starting doses with an open-label, dose-finding phase with five patients in each cohort. During the dose-finding phase, patients aged 6-17 years started eltrombopag at 25 mg once per day (12·5 mg for those weighing <27 kg) and patients aged 1-5 years received 0·7 mg/kg per day to a maximum of 2 mg/kg unless otherwise approved. We permitted dose adjustments on the basis of platelet response up to a maximum dosage of 75 mg per day. Additional patients were then recruited and randomly assigned (2:1) to receive either eltrombopag or placebo tablets (or oral suspension formulation if aged 1-5 years) once per day for 7 weeks at the previously established doses. Starting doses for the double-blind phase were 37·5 mg/day for patients aged 12-17 years; 50 mg/day for patients weighing 27 kg or more (25 mg for east Asian patients) and 25 mg/day for patients weighing less than 27 kg (12·5 mg once per day for east Asian patients) for patients aged 6-11 years; and 1·5 mg/kg once per day (0·8 mg/kg once per day for east Asian patients) for patients aged 1-5 years. Randomisation was done by the GlaxoSmithKline Registration/Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who completed treatment were then enrolled into an open-label phase and all patients could receive up to 24 weeks of eltrombopag. The primary outcome was the proportion of patients achieving a platelet count of 50 × 10(9) per L or more at least once from weeks 1-6 (days 8 to 43) of the randomised phase of the study in the absence of rescue therapy. We assessed efficacy in the intent-to-treat population, which consisted of all patients assigned to treatment, and we assessed safety in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT00908037.
FINDINGS: Between Oct 2, 2009, and June 22, 2011, we recruited 15 patients, with five patients in each age cohort, into the open-label dose-finding phase who did not progress into the double-blind phase. From March 17, 2010, to Jan 15, 2013, we randomly assigned 67 patients to treatment, with 45 patients assigned to receive eltrombopag (16 children aged 12-17 years, 19 aged 6-11 years, and ten aged 1-5 years) and 22 to receive placebo (eight children aged 12-17 years, nine aged 6-11 years, and five aged 1-5 years). However, two patients assigned to receive eltrombopag did not receive the study drug and one was lost to follow-up, and one patient assigned to receive placebo was given eltrombopag. From weeks 1 to 6, 28 (62%) patients who received eltrombopag, compared with seven (32%) who received placebo, achieved the primary endpoint of platelet count 50 × 10(9) per L or more at least once without rescue (odds ratio 4·31, 95% CI 1·39-13·34, p=0·011). The most common adverse events with eltrombopag were headache (13 [30%] patients receiving eltrombopag vs nine [43%] patients receiving placebo), upper respiratory tract infection (11 [25%] patients vs two [10%] patients), and diarrhoea (seven [16%] patients vs one [5%] patient). Grade 3 or 4 adverse events occurred in five (11%) patients receiving eltrombopag and four (19%) patients receiving placebo, and serious adverse events (four [9%] patients receiving eltrombopag and two (10%) patients receiving placebo) were similarly infrequent in both groups. No thrombotic events or malignancies occurred. Increased alanine aminotransferase concentrations caused two (3%) of 65 patients to discontinue eltrombopag in the open-label phase.
INTERPRETATION: Our results showed that eltrombopag could be used to increase platelet counts and reduce clinically significant bleeding in children with persistent or chronic immune thrombocytopenia. Prevalence of increased liver laboratory values was similar to that seen in adults.
FUNDING: GlaxoSmithKline.
Phase II, multi-center, 3 part, staggered cohort, open-label and double blind, randomized, placebo controlled study involving 3 age-determined cohorts (Cohort 1: between 12 and 17 years old; Cohort 2: between 6 and 11 years old; Cohort 3: between 1 and 5 years old). Daily dosing with eltrombopag will begin with 5 patients in the oldest age cohort in an open label fashion, and a review of safety, pharmacokinetic and platelet count data will be performed regularly. If no safety concerns are identified after 12 weeks, 18 additional patients will be randomised to placebo or eltrombopag (2:1 randomisation). After 7 weeks of randomized treatment, all patients will receive eltrombopag in an open label fashion. The total duration of treatment with eltrombopag will be 24 weeks. If at the time of the aforementioned 12 week review of the first 5 patients no safety issues are identified, dosing will begin in the next lower age cohort with an initial group of 5 patients. The same procedure will be followed in terms of safety review and subsequent enrolment and randomisation of the additional patients. Initiation of the younger age cohort will take place once data from the previous has been evaluated. Doses will be adjusted according to platelet counts and tolerability. The study will include a review of the safety data by a Data Safety Monitoring Board.
