Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia

Abstract

Avatrombopag, an oral thrombopoietin receptor agonist, was compared with placebo in a 6-month, multicentre, randomised, double-blind, parallel-group Phase 3 study, with an open-label extension phase, to assess the efficacy and safety of avatrombopag (20 mg/day) in adults with chronic immune thrombocytopenia (ITP) and a platelet count <30 × 10⁹ /l (ClinicalTrials.gov identifier NCT01438840). The primary endpoint was the cumulative number of weeks of platelet response (platelet count ≥50 × 10⁹ /l) without rescue therapy for bleeding; secondary endpoints included platelet response rate at day 8 and reductions in the use of concomitant medications. Amongst the 49 patients randomised, avatrombopag (N = 32) was superior to placebo (N = 17) in the median cumulative number of weeks of platelet response (12·4 vs. 0·0 weeks, respectively; P < 0·0001). At day 8, a greater platelet response rate was also observed for patients treated with avatrombopag compared with placebo (65·63% vs. 0·0%; P < 0·0001), and use of concomitant ITP medications was also reduced amongst patients receiving avatrombopag. The safety profile of avatrombopag was consistent with Phase 2 studies; the most common adverse events were headache and contusion. Overall, avatrombopag was well tolerated and efficacious for the treatment of chronic ITP.

Keywords: bleeding disorders; platelet count; platelet disorders; thrombocytopenia; thrombopoietin.

Figure 1

Study design. (A) Core study. (B) Extension phase. AVA, avatrombopag; CONMED, concomitant medication; E, extension; EOT, end‐of‐treatment; ITP, immune thrombocytopenia; PBO, placebo; qd, once‐daily; R, randomised. *At EOT visit (visit 22), patients could enter the extension phase and receive open‐label avatrombopag therapy. Patients who did not continue into the extension phase entered the dose‐tapering and follow‐up phase. ^†Only for patients who did not enter the extension phase. ^‡Optional entry into the open‐label extension phase. ^§The screening visit and day 1 baseline/randomisation visit platelet counts were averaged to obtain the baseline platelet count value. The two samples were obtained ≥48 h and ≤2 weeks apart and the results were available prior to randomisation. Therefore, an additional screening platelet count may have been required due to issues with scheduling. ^‖Patients who discontinued early who met the criteria for a lack of treatment effect may have moved directly into the open‐label extension phase. [Colour figure can be viewed at http://wileyonlinelibrary.com]

Figure 2

Subject disposition. (A) Core study. (B) Extension phase. N/n, number of patients. [Colour figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

Median (Q1, Q3) platelet count over time. (A) Core study (FAS). (B) Extension phase (modified FAS). FAS, full analysis set; ITP, immune thrombocytopenia; Med, medication; n, number of patients; Q1/3, quartile 1/3. [Colour figure can be viewed at http://wileyonlinelibrary.com]