Analysis of Bleeding in Patients with Immune Thrombocytopenic Purpura (ITP): A Randomized, Double-Blind, Placebo-Controlled Trial of Eltrombopag, an Oral Platelet Growth Factor.

Abstract Thrombocytopenia in ITP is due to both increased platelet clearance and inadequate platelet production. Bleeding episodes may occur as a result of the thrombocytopenia. Increasing the platelet count in patients with ITP may prevent or decrease bleeding episodes. Eltrombopag is an oral thrombopoietin receptor agonist that stimulates proliferation and differentiation of megakaryocytes and progenitor cells, ultimately increasing the number of circulating platelets. The safety and efficacy of eltrombopag were evaluated in an international, randomized, double-blind, placebo-controlled, phase II trial in adults with chronic, previously-treated ITP and platelets <30,000/mL. Subjects were randomized (1:1:1:1) to placebo, 30mg, 50mg, or 75mg eltrombopag once daily for 6 weeks; study medication was discontinued in patients whose platelet counts exceeded 200,000/mL during the 6 week doing period. Subjects were followed for 6 more weeks after discontinuation of study medication. Bleeding was assessed weekly during treatment and biweekly after discontinuation via the World Health Organization (WHO) bleeding scale and adverse event reporting. The WHO bleeding scale measures bleeding severity: Grade 0 (no bleeding), Grade 1 (mild), Grade 2 (moderate), Grade 3 (gross) and Grade 4 (debilitating blood loss). The intent-to-treat analysis included 117 subjects; 29 on placebo and 30, 30, and 28 on the 30mg, 50mg and 75mg eltrombopag arms, respectively. There was a dose-dependent increase in the proportion of responders (platelet counts ≥ 50,000/μL) with a statistically significant effect in the 50mg and 75mg arms compared to placebo. The median platelet count on day 43 was 16,000/μL in the placebo group and 26,000/μL, 128,000/μL and 183,000/μL in the 30mg, 50mg, and 75mg eltrombopag arms, respectively. Preliminary analysis suggested a trend of decreased bleeding incidence (all grades) measured in subjects treated with 50mg and 75mg eltrombopag. On therapy bleeding adverse events included the following: hemorrhoids, hemorrhagic diarrhea and conjunctival hemorrhage in 3 placebo patients; epistaxis, gingival bleeding and contusions in 5 of the 30mg patients; menorrhagia in 1 50mg patient (who did not respond to eltrombopag); and contusion in 1 75mg patient. Bleeding adverse events following discontinuation of treatment included: hemorrhoidal hemorrhage, epistaxis, menometrorrhagia and menorrhagia in 4 placebo patients; gingival bleeding, conjunctival hemorrhage, contusion and epistaxis in 4 30mg patients; rectal hemorrhage, menstrual disorder and petechiae in 3 50mg patients; and petechiae and menorrhagia in 2 75mg patients. The incidence of on therapy bleeding events regardless of grade and causality was 10% in the placebo and 16%, 3% and 4% in the 30mg, 50mg and 75mg eltrombopag arms, respectively. The incidence of off therapy bleeding events was 14% on the placebo arm, 13% on the 30mg arm, 10% on the 50mg arm and 7% on the 75mg arm. Based on the encouraging efficacy and safety data generated in this study, further phase III studies with eltrombopag have been initiated.