Lusutrombopag for the Treatment of Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Invasive Procedures (L-PLUS 2)

Abstract

Thrombocytopenia may be associated with increased bleeding risk impacting timing and outcome of invasive procedures in patients with chronic liver disease (CLD). Lusutrombopag, a small-molecule, thrombopoietin (TPO) receptor agonist, was evaluated as a treatment to raise platelet counts (PCs) in patients with thrombocytopenia and CLD undergoing invasive procedures. L-PLUS 2 was a global, phase 3, randomized, double-blind, placebo-controlled study. Adults with CLD and baseline PCs < 50 × 10⁹ /L were randomized to receive once-daily lusutrombopag 3 mg or placebo ≤ 7 days before an invasive procedure scheduled 2-7 days after the last dose. The primary endpoint was avoidance of preprocedure platelet transfusion and avoidance of rescue therapy for bleeding. A key secondary endpoint was number of days PCs were ≥ 50 × 10⁹ /L throughout the study. Safety analysis was performed on patients who received at least one dose of study drug. This study occurred between June 15, 2015, and April 19, 2017, with a total of 215 randomized patients (lusutrombopag, 108; placebo, 107); 64.8% (70/108) of patients in the lusutrombopag group versus 29.0% (31/107) in the placebo group met the primary endpoint (P < 0.0001; difference of proportion 95% confidence interval [CI], 36.7 [24.9, 48.5]). The median duration of PCs ≥ 50 × 10⁹ /L was 19.2 days with lusutrombopag (without platelet transfusion) compared with 0.0 in the placebo group (with platelet transfusion) (P = 0.0001). Most adverse events were mild or moderate in severity, and rates were similar in the lusutrombopag and placebo groups (47.7% and 48.6%, respectively). Conclusion: Lusutrombopag was superior to placebo for reducing the need for platelet transfusions and achieved durable PC response in patients with thrombocytopenia and CLD undergoing invasive procedures, with a safety profile similar to placebo.

Figure 1

L‐PLUS 2 trial design. Abbreviations: CT, computed tomography; ICF, informed consent form; MRI, magnetic resonance imaging; US, ultrasonography.

Figure 2

Trial profile. ^*Includes noncompliance with preprocedure platelet transfusion instructions or out of window of preprocedure platelet transfusion assessment. ^†Includes subjects receiving less than 5 days of study drug but did not fulfill the stopping criterion for study drug or no study drug administration. ^‡Includes Child‐Pugh class C, received other TPO receptor agonist, or PC > 50 × 10⁹/L at baseline on day 1 before randomization.

Figure 3

Proportion of patients in the lusutrombopag and placebo groups meeting the primary efficacy endpoint in ITT and PP populations.

Figure 4

Subgroup analysis for the difference in the proportion of patients in the lusutrombopag and placebo groups meeting the primary efficacy endpoint for (A) ITT (prespecified analysis) and (B) PP (post hoc analysis) populations. Primary endpoint is proportion of patients who required no platelet transfusion before invasive procedure and no rescue therapy for bleeding from randomization through 7 days after the procedure. In addition to patients who received platelet transfusion, patients who did not receive an invasive procedure regardless of the reason were considered as receiving platelet transfusion. The Wald‐type CIs were calculated.

Figure 5

Median PCs over time for patients treated with lusutrombopag (without platelet transfusion) or placebo (with platelet transfusion). Error bars indicate 25th percentile and 75th percentile.