A phase 3, randomized, double‐blind, active‐controlled trial evaluating efficacy and safety of avatrombopag versus eltrombopag in ITP

No clinical studies have directly compared thrombopoietin receptor agonists (TPO-RAs) to other immune thrombocytopenia (ITP) treatments or to each other. This double-blind, randomized active-controlled study of avatrombopag versus eltrombopag conducted in adults with chronic primary ITP was intended to be the first direct comparison of TPO-RAs. Patients were randomized 1:1 to receive avatrombopag (5–40 mg daily) or eltrombopag (25–75 mg daily). The core study design is shown in Figure S1. Specific dosing levels, guidance for use of rescue therapy, and reasons for treatment discontinuation are presented in Text S1. Inclusion and exclusion criteria and allowable concomitant medications are shown in Table S1 and Text S2, respectively. Because of gastrointestinal concerns described in the accompanying report,1 the US Food and Drug Administration (FDA) required that the initial study protocol include endoscopic evaluations, accompanied by laboratory testing, in patients with platelet counts >50 × 109/L, as safety assessments. A preclinical study had reported changes in the gastric glandular epithelium of rats receiving a very high avatrombopag dose (exposures equivalent to ≥14 times the area under the curve compared to patients who received a 60-mg daily dose of avatrombopag).2 Such gastric adverse events (AEs) have not been observed in humans and these assessments were a tremendous barrier to enrollment; therefore, eventually, the requirement for endoscopy was removed in a later protocol amendment (June 15, 2012). However, approval delays with IRB protocol amendments resulted in reduced interest from study sites; the study was terminated by the study sponsor (Eisai Inc.) for poor accrual on 22 January 2013. The study goal was to compare efficacy of avatrombopag to eltrombopag as measured by durable platelet response during the last 8 weeks of treatment of the 6-month treatment period in the absence of rescue therapy. Secondary outcomes were efficacy of avatrombopag and eltrombopag by platelet response at Day 8 and bleeding events along with safety evaluation (laboratory monitoring and recording of AEs [Medical Dictionary for Regulatory Activities, version 16.0]). The rationale for the planned sample size of 286 patients and the originally planned statistical considerations are presented in Text S3. Patients were screened at 15/61 participating sites worldwide. Ten sites enrolled and treated the 23 entered patients (Figure S2). Reasons for study discontinuation (other than study termination) were AE in 1 patient (avatrombopag) and inadequate therapeutic effect in 1 (avatrombopag) and 5 (eltrombopag) patients. At Week 6, 11/12 patients on avatrombopag and 9/11 patients on eltrombopag continued in the trial; this dropped to 8 and 4, respectively, at Week 8. The prespecified analyses could not be performed given the limited enrollment and short duration of patient participation, so post hoc descriptive analyses were conducted instead using data up to 6 weeks of treatment. At baseline, median (min, max) platelet counts were comparable in the avatrombopag (n = 12) and eltrombopag (n = 11) groups (8.5 [3.0, 27.5] × 109/L and 15.0 [9.0, 29.5] × 109/L) (Table S2). At Week 6, the median (min, max) platelet counts were 117.0 (9.0, 407.0) × 109/L on avatrombopag (n = 11) and 48.0 (8.0, 157.0) × 109/L on eltrombopag (n = 7) (Table S3). The mean daily dose of avatrombopag (data available for 8 patients) was ≤10 mg for 1 patient (12.5%), >10 mg to ≤20 mg for 4 (50%), >20 mg to ≤30 mg for 2 (25%), and >30 mg for 1 (12.5%). The mean daily dose of eltrombopag (n = 11) was >25 mg to ≤50 mg for 5 patients (45.5%) and >50 mg for 6 (54.5%). Maximum daily dose is shown in Figure S3. At Day 8, the median platelet counts for the avatrombopag and eltrombopag arms were 40.0 × 109/L and 25.0 × 109/L (Table S3), and 5/11 vs. 4/11 of patients achieved platelet counts ≥50 × 109/L at Day 7 or 8. Individual platelet counts up to Week 6 are shown in Figure 1. Nine patients (75.0%) on avatrombopag and 8 (72.7%) on eltrombopag experienced treatment-related TEAEs, with a respective 3/12 and 3/11 experiencing Grade 3 or 4 TEAEs (Table S4). On avatrombopag, Grade 3 or 4 TEAEs were nausea (Grade 3; probably related to study drug) and vomiting (Grade 3; probably related) in 1 patient; infective (Moraxella) exacerbation of chronic obstructive pulmonary disease (COPD) (Grade 3; unrelated), acute exacerbation of COPD (Grade 3; unrelated), and spontaneous pneumothorax (Grade 4; unrelated) in 1 patient; and portal vein thrombosis (Grade 3; possibly related) and infective/septic thrombophlebitis (Grade 3; possibly related) in 1 patient. On eltrombopag, Grade 3 or 4 TEAEs were general discomfort (Grade 3; probably related), hypophosphatemia (Grade 3; unrelated) and asthenia (Grade 3; unrelated) in 1 patient each. Grade 1 or 2 bleeding events occurred in 6 patients on avatrombopag and 9 patients on eltrombopag (Table S5). No deaths occurred. This study had major limitations beyond its limited enrollment and early termination. All patients were required to take 2 sets of medication and maintain the dietary limitations needed for eltrombopag (no food 1 h before/2 h after dosing); poor compliance may have biased the results against eltrombopag since the response was lower than in previous trials. The major limitation to enrollment was the requirement for endoscopy during the study if elevations in gastric biomarkers occurred. This was especially problematic for patients with no gastrointestinal symptoms and very low platelet counts (i.e. those at a level required to enrol in the study); as a result, many investigators refused to enter patients. The gastric findings in animal studies,2 which were the basis of this request by the FDA, are often not well-correlated with findings in people.3 A concurrently published letter from our group reports a combined analysis of patients from this and another phase 3 study who received chronic avatrombopag dosing and were screened by biomarkers for atrophic gastritis.1 Minor elevations in gastric biomarkers were reported in a few patients but nothing requiring additional action or cessation of treatment. Given the insufficient enrollment in this study, it was not possible to demonstrate non-inferiority of avatrombopag versus eltrombopag. Michael D. Tarantino, James B. Bussel and Eun-Ju Lee served as study investigators. Brian D. Jamieson participated in data analysis. All authors contributed to data interpretation and participated in the preparation of the manuscript. All authors participated in the critical review and revision of this manuscript. All authors approved the manuscript for submission. Editorial support, specifically assistance with manuscript writing and styling, was provided by Michael R. Page, PharmD, RPh, and Sarah S. Bubeck, PhD, of BioCentric, Inc., and funded by Sobi, Inc. This study was funded by Eisai Inc., and medical writing support was funded by Sobi, Inc., Durham, NC. The funder, Eisai Inc., designed the study and was involved in the analysis and interpretation of data. Sobi, Inc., Durham, NC, was involved the analysis and interpretation of data, in the preparation of the manuscript, and in the decision to submit the manuscript for publication. Michael D. Tarantino: Chief Medical and Chief Executive Officer of the Bleeding and Clotting Disorders Institute; owner and president of Michael D. Tarantino, MD SC, a private medical practice; serves on speakers' bureaus for Amgen, BioMarin, Genentech, Grifols, Octapharma, Sobi, and Takeda; and serves as a private consultant for Amgen, BioMarin, Genentech, Octapharma, Principia, Sobi, Takeda, and UCB. James B. Bussel: consultant/ad board attendee for Amgen, Novartis, Sobi, Rigel, UCB, Janssen, argenx, AstraZeneca and Rallybio and is on a Data and Safety Monitoring Board at UCB. Eun-Ju Lee: advisory board member/consultant for UCB and Pharmacosmos. Brian D. Jamieson: employee of Sobi, Inc., Durham, NC. This study complied with International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practice and all applicable local regulations. The study protocol was approved by institutional review boards (IRBs) or ethics committees at each study site. All patients provided written informed consent prior to study enrollment. ClinicalTrials.gov, registration number NCT01433978. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.