Avatrombopag, an Alternate Treatment Option to Reduce Platelet Transfusions in Patients with Thrombocytopenia and Chronic Liver Disease-Integrated Analyses of 2 Phase 3 Studies (original) (raw)
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Gastroenterology, 2018
Patients with thrombocytopenia and chronic liver disease (CLD) may require platelet transfusions before scheduled procedures to decrease risk of bleeding. We performed 2 randomized, placebo-controlled, phase 3 trials in patients with thrombocytopenia and CLD undergoing scheduled procedures to evaluate the safety and efficacy of avatrombopag in increasing platelet counts in this patient population METHODS: In the ADAPT-1 and ADAPT-2 studies, adults with thrombocytopenia and CLD (n=231 and n= 204, respectively) were in 1 of 2 cohorts according to their baseline platelet count (below 40x10/L or 40-50x10/L) and within each cohort randomized (2:1) to 5 daily doses of avatrombopag (60 mg if baseline platelet count below 40x10/L or 40 mg if 40-50x10/L) or placebo. ADAPT-1 was conducted at 75 study sites in 20 countries, from February 2014 through January 2017 and ADAPT-2 was conducted at 74 sites in 16 countries, from December 2013 through January 2017. The primary endpoint was the proport...
Journal of hepatology, 2014
This is a phase II multicentre study to investigate the efficacy and safety of avatrombopag (E5501), an investigational second-generation thrombopoietin receptor agonist, administered one week prior to elective procedures in patients with thrombocytopenia secondary to cirrhosis. Adults with cirrhosis and platelet counts ⩾10 to ⩽58×10(9)/L were randomized to placebo or avatrombopag in two sequential cohorts. Cohort A: placebo vs. one of 3 different doses (100mg loading dose followed by 20, 40, or 80 mg/day on days 2-7) of a first-generation avatrombopag formulation. Cohort B: placebo vs. one of 2 different doses (80 mg loading dose followed by 10 mg/day for days 2-7, or 20mg/day for days 2-4) of a second-generation avatrombopag formulation. Primary end point was achievement of a platelet increase of ⩾20×10(9)/L from baseline and >50×10(9)/L at least once during days 4-8. A total of 130 patients were randomized: 93 patients (51, cohort A; 42, cohort B) to avatrombopag and 37 (16, c...
Hepatology, 2019
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 × 10 9 /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 × 10 9 /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 × 10 9 /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.
Hepatology Research, 2019
Lusutrombopag is approved for the treatment of thrombocytopenia in chronic liver disease patients undergoing invasive procedures. This real-world surveillance assesses the safety and effectiveness of lusutrombopag in Japan. Methods: This ongoing, multicenter, prospective, real-world surveillance is collecting data from case report forms between October 2016 and May 2021. Interim data up to September 2018 were used to evaluate safety (adverse events and adverse drug reactions [ADRs]) and effectiveness (proportion of patients avoiding preoperative platelet transfusion and change in platelet count from baseline). Results: The safety analysis set included 331 patients. The mean baseline platelet count was 46.2 ± 13.7 × 10 9 /L. Of 377 invasive procedures, radiofrequency ablation (110 procedures, 29.2%) was the most frequent. The mean time from starting lusutrombopag treatment to invasive procedure was 12.3 days. Incidences of serious adverse events and ADRs were 8.76% and 3.32%, respectively. Six cases (1.81%) of portal vein thrombosis were considered serious adverse events; of these, four cases (1.21%) were classified as serious ADRs. Of 300 patients who underwent an invasive procedure (excluding those with platelet transfusion refractoriness), 282 (94.0%) avoided preoperative platelet transfusion. In patients with platelet measurements before and after lusutrombopag administration who did not undergo platelet transfusion, the mean maximum change in platelet count from baseline was 41.7 ± 31.4 × 10 9 /L (range, À6 to 276; n = 286). All patients receiving second (n = 20) and third (n = 1) treatments avoided preoperative platelet transfusion without developing any ADRs. Conclusions: This real-world surveillance further supports the safety and effectiveness of lusutrombopag in patients with chronic liver disease undergoing invasive procedures.
Eltrombopag before Procedures in Patients with Cirrhosis and Thrombocytopenia
New England Journal of Medicine, 2012
Eltrombopag is an oral thrombopoietin-receptor agonist. This study evaluated the efficacy of eltrombopag for increasing platelet counts and reducing the need for platelet transfusions in patients with thrombocytopenia and chronic liver disease who are undergoing an elective invasive procedure. We randomly assigned 292 patients with chronic liver disease of diverse causes and platelet counts of less than 50,000 per cubic millimeter to receive eltrombopag, at a dose of 75 mg daily, or placebo for 14 days before a planned elective invasive procedure that was performed within 5 days after the last dose. The primary end point was the avoidance of a platelet transfusion before, during, and up to 7 days after the procedure. A key secondary end point was the occurrence of bleeding (World Health Organization [WHO] grade 2 or higher) during this period. A platelet transfusion was avoided in 104 of 145 patients who received eltrombopag (72%) and in 28 of 147 who received placebo (19%) (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). No significant difference between the eltrombopag and placebo groups was observed in bleeding episodes of WHO grade 2 or higher, which were reported in 17% and 23% of patients, respectively. Thrombotic events of the portal venous system were observed in 6 patients who received eltrombopag, as compared with 1 who received placebo, resulting in the early termination of the study. The incidence and severity of other adverse events were similar in the eltrombopag and placebo groups. Eltrombopag reduced the need for platelet transfusions in patients with chronic liver disease who were undergoing elective invasive procedures, but it was associated with an increased incidence of portal-vein thrombosis, as compared with placebo. (Funded by GlaxoSmithKline; ELEVATE ClinicalTrials.gov number, NCT00678587.).
Journal of Medical Economics
Background: Thrombocytopenia (TCP), a common complication of chronic liver disease (CLD), can cause uncontrolled bleeding during procedures. As such, CLD patients with TCP and platelet counts <50,000/μL often receive prophylactic platelet transfusions before invasive procedures. However, platelet transfusions are associated with clinical complications, which may result in increased healthcare utilization and costs. Objective: This retrospective database analysis describes the clinical and economic burden in CLD patients with TCP, CLD patients without TCP, and CLD patients with TCP who receive platelet transfusions. Methods: Adult CLD patients with or without TCP were identified in the IBM MarketScan®
The Lancet, 2009
Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that stimulates thrombopoiesis, leading to increased platelet production. This study assessed the efficacy, safety, and tolerability of once daily eltrombopag 50 mg, and explored the efficacy of a dose increase to 75 mg. In this phase III, randomised, double-blind, placebo-controlled study, adults from 63 sites in 23 countries with chronic idiopathic thrombocytopenic purpura (ITP), platelet counts less than 30 000 per muL of blood, and one or more previous ITP treatment received standard care plus once-daily eltrombopag 50 mg (n=76) or placebo (n=38) for up to 6 weeks. Patients were randomly assigned in a 2:1 ratio of eltrombopag:placebo by a validated randomisation system. After 3 weeks, patients with platelet counts less than 50 000 per microL could increase study drug to 75 mg. The primary endpoint was the proportion of patients achieving platelet counts 50 000 per microL or more at day 43. All participants who received at least one dose of their allocated treatment were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00102739. 73 patients in the eltrombopag group and 37 in the placebo group were included in the efficacy population and were evaluable for day-43 analyses. 43 (59%) eltrombopag patients and six (16%) placebo patients responded (ie, achieved platelet counts &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;/=50 000 per microL; odds ratio [OR] 9.61 [95% CI 3.31-27.86]; p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001). Response to eltrombopag compared with placebo was not affected by predefined study stratification variables (baseline platelet counts, concomitant ITP drugs, and splenectomy status) or by the number of previous ITP treatments. Of the 34 patients in the efficacy analysis who increased their dose of eltrombopag, ten (29%) responded. Platelet counts generally returned to baseline values within 2 weeks after the end of treatment. Patients receiving eltrombopag had less bleeding at any time during the study than did those receiving placebo (OR 0.49 [95% CI 0.26-0.89]; p=0.021). The frequency of grade 3-4 adverse events during treatment (eltrombopag, two [3%]; placebo, one [3%]) and adverse events leading to study discontinuation (eltrombopag, three [4%]; placebo, two [5%]), were similar in both groups. Eltrombopag is an effective treatment for managment of thrombocytopenia in chronic ITP.
Avatrombopag for the treatment of immune thrombocytopenia
Expert Review of Clinical Immunology, 2019
Introduction: Thrombopoietin-receptor agonists (TPO-RAs) are the only American Society of Hematology (ASH) guideline-advocated, second-line treatment for immune thrombocytopenia (ITP) that have been validated by randomized, controlled trials with a placebo comparator. Avatrombopag is a new candidate in this class that has been investigated as a treatment option for the treatment of ITP. Areas covered: In this Drug Profile, we provide a review of the clinical data of avatrombopag, which was approved in May 2018 by the Unites States Food and Drug Administration (FDA) for the treatment of thrombocytopenia in patients with chronic liver disease undergoing an invasive procedure, and an opinion of its potential place in the current evidence-based ITP treatment landscape. Expert commentary: Avatrombopag induces doubling of platelet counts, increasing them to above 50 X 109/L, and prevents the need for platelet transfusions while minimizing the need for rescue medications. Treatment-emergent adverse events (TEAEs) are comparable to placebo. Oral delivery, a 5-day dosing schedule and good tolerability (<1% discontinuation rate) with no clinically significant hepatoxicity make it a promising entrant as a potential second-line treatment for ITP. Further, data from a phase 3 study in patients with ITP supports its utility in the treatment of patients with ITP.
GastroHep, 2019
Background: Platelet transfusions (PT) are the standard of care for thrombocytopenia in patients with chronic liver disease (CLD) who are at risk for bleeding when undergoing planned invasive procedures (PIP). In addition to PTs having short term effectiveness, PTs Accepted Article This article is protected by copyright. All rights reserved. are associated with complications (transfusion-associated circulatory overload [TACO], transfusion-related acute lung injury [TRALI]) and increased healthcare resource utilization [HCRU]). Objective: To characterize the clinical and economic burden among CLD patients who receive a PT for their PIP. Methods: A retrospective analysis was performed using MarketScan® research databases. A PT-related population that consisted of patients who received a PT for their PIP and a non-PT-related population diagnosed with thrombocytopenia that did not receive a PT for their PIP were derived. Each PT-related patient was matched with 1 to 3 non-PT-related patients on factors predictive of severity of liver disease and increased HCRU. Results: After applying the inclusion criteria and patient-matching, 210 patients were included in the PT-related population and 564 patients were included in the non-PT-related population. PT-related patients had an increase (mean increase: 11.1K;medianincrease:11.1K; median increase: 11.1K;medianincrease:2.1K) in payments received between admission date of the PIP-related hospitalization and 30 days after discharge. PT-related patients also had a higher proportion of bleeding events