Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE)
Authors: Cheng Gregory , Saleh Mansoor N , Bussel James B , Marcher Claus , Vasey Sandra , Mayer Bhabita , Aivado Manuel , Arning Michael , Stone Nicole L. 
Published: April 2020

INTRODUCTION: Eltrombopag (PROMACTA®/REVOLADE®; GlaxoSmithKline, Collegeville, PA, USA) is a first-in-class, oral, small molecule, non-peptide, thrombopoietin receptor agonist being studied for the treatment of thrombocytopenia related to a variety of conditions.

METHODS: RAISE was a 6-month, randomized, double-blind, placebo-controlled, phase III study that evaluated the efficacy and safety of eltrombopag in previously treated adults with chronic idiopathic thrombocytopenic purpura (ITP) with platelet counts &lt;30,000/μL. It was estimated that approximately 189 patients randomized 2:1 (eltrombopag:placebo) would provide sufficient statistical power. Patients were stratified by splenectomy status, use of baseline ITP medication, and platelets □15,000/μL. Patients initiated treatment with eltrombopag 50 mg (or matching placebo) once daily, and the dose was individualized based upon each patient’s platelet response, from a maximum of 75 mg once daily to 25 mg once daily or less frequently. Patients could reduce concomitant medications and receive rescue therapy as dictated by local standard of care. The primary endpoint was the odds of responding (platelets 50,000 to 400,000/μL) during the treatment period for patients receiving eltrombopag relative to placebo. Bleeding symptoms were prospectively evaluated using the WHO Bleeding Scale: Grade 0 = no bleeding, Grade 1 = mild bleeding, Grade 2 = moderate bleeding, Grade 3 = gross bleeding, and Grade 4 = debilitating blood loss.

RESULTS: One hundred ninety-seven patients (eltrombopag, 135; placebo, 62) were enrolled in RAISE, and baseline characteristics were balanced: in both arms ~50% of patients had platelet counts □15,000/μL, ~50% were receiving concomitant ITP therapies, ~35% were splenectomized, and &gt;15% had received at least 3 prior ITP medications. Patients who received eltrombopag were 8 times more likely to achieve platelet counts 50,000 to 400,000/μL during the 6-month treatment period compared with patients on placebo (OR [95% CI] = 8.2 [4.32, 15.38]; P &lt;0.001). Baseline median platelet counts were 16,000/μL in both groups and never exceeded 30,000/μL in the placebo group. In contrast, platelets rose to 36,000/μL after 1 week in the eltrombopag group (Figure 1) and subsequently ranged from 52,000 to 91,000/μL for the remainder of the study. Median platelet counts returned to near baseline 2 weeks after stopping eltrombopag. Patients responded to eltrombopag regardless of splenectomy status, use of baseline ITP medications, or baseline platelet counts. Significantly fewer patients treated with eltrombopag had any bleeding (WHO Grades 1–4; P &lt;0.001) or clinically significant bleeding (WHO Grades 2–4; P &lt;0.001) throughout the trial compared with patients treated with placebo. More patients in the eltrombopag group (59%) stopped or dose-reduced their concomitant ITP medications than in the placebo group (32%; P = 0.016). Patients in the eltrombopag group (19%) required less rescue therapy compared with the placebo group (40%; P = 0.001) during the treatment phase of the study. The overall incidence of adverse events (AEs) was similar between the eltrombopag (87%) and placebo groups (92%), and the AEs were mostly mild to moderate. Headache was the most common AE in both groups (30%). Of note, 2 steroid-associated AEs (dyspepsia and peripheral edema) were significantly less likely to occur in the eltrombopag group compared with the placebo group. A higher incidence of hepatobiliary laboratory abnormalities were reported in the eltrombopag group (13%) compared with the placebo group (7%). There were no clinical or laboratory symptoms suggestive of bone marrow fibrosis. One death due to brain stem hemorrhage was reported in the placebo group.

DISCUSSION: Long-term eltrombopag therapy significantly increased platelet counts, decreased bleeding symptoms, allowed for a reduction or discontinuation of baseline ITP therapies, and reduced the use of rescue ITP medications compared with placebo. Eltrombopag was well-tolerated, with a similar safety profile to placebo, and is an important new treatment option for patients with chronic ITP.

Figure 1. Median platelet counts.a&#x2028; BL, median baseline value.&#x2028; aError bars represent the 25th to 75th percentiles for each treatment group. Figure 1. Median platelet counts.a&#x2028; BL, median baseline value.&#x2028; aError bars represent the 25th to 75th percentiles for each treatment group.