Assessing the periprocedural magnitude of platelet count change in response to lusutrombopag.

BACKGROUND & AIMS: Despite limitations, platelet transfusion has been used to minimise bleeding risk in patients with thrombocytopaenia. Lusutrombopag is an oral, thrombopoietin receptor agonist approved for treatment of thrombocytopaenia associated with chronic liver disease in patients undergoing planned invasive procedures. This post-hoc analysis assessed the magnitude of platelet count change based on the integrated per-protocol population from 2 similar phase III multicentre, randomised, double-blind, placebo-controlled trials. METHODS: Adults with chronic liver disease-induced thrombocytopaenia and platelet count <50 (× 109/L) received lusutrombopag 3 mg or placebo ≤7 days before invasive procedure scheduled 9-14 days after randomisation. Platelet transfusion was required per protocol if the platelet count remained <50 no more than 2 days before the planned invasive procedure. Post-hoc analysis included: proportion of patients with platelet count ≥50, ≥1.5-fold increase, and a doubling of platelet count; maximum and maximum change in platelet count; and platelet count time course. RESULTS: Platelet count ≥50, a platelet count increase ≥1.5-fold, and at least a doubling in platelet count were achieved in 88.3%, 86.9%, and 52.6% of patients in the lusutrombopag group (n = 137) vs. 58.6%, 32.3%, and 6.0% of patients in the placebo group (n = 133), respectively. In the lusutrombopag group, median maximum platelet count across baseline platelet counts of <30, ≥30 to <40, and ≥40 was 46, 76, and 87, respectively. Median maximum change in platelet count by baseline platelet count was +24, +42, and +40, respectively. Patients who received lusutrombopag without platelet transfusion achieved a median platelet count ≥50 for 3 weeks. CONCLUSIONS: Patients treated with lusutrombopag experienced a clinically relevant response in platelet count for a substantial duration of time. LAY SUMMARY: Patients with low platelet counts caused by chronic liver disease may not receive planned invasive procedures or surgeries because of an increased risk of bleeding. Lusutrombopag has previously demonstrated efficacy in raising platelet counts and is approved to treat chronic liver disease patients with low platelet counts in advance of a planned surgery. Physicians need to understand more clearly what to expect in terms of platelet count change when using lusutrombopag; this integrated analysis provides data to help guide its clinical application.

Lusutrombopag Is Safe and Efficacious for Treatment of Thrombocytopenia in Patients With and Without Hepatocellular Carcinoma.

BACKGROUND & AIMS: Patients with hepatocellular carcinoma (HCC) secondary to chronic liver disease often require invasive procedures but frequently have thrombocytopenia. Lusutrombopag is an agonist of the thrombopoietin receptor that activates platelet production. METHODS: We performed an integrated analysis of data from 2 phase 3 trials (L-PLUS 1, Japan, October 2013 to May 2014, and L-PLUS 2, global, June 2015 to April 2017) that compared the efficacy and safety of lusutrombopag with placebo in patients with chronic liver disease, with and without HCC. Our analysis included patients with Eastern Cooperative Oncology Group grades of 0 or 1, Child-Pugh classes A or B, and a platelet count less than 50 × 109/L who were scheduled to undergo invasive procedures in 9 to 14 days. Patients received lusutrombopag (3 mg) or placebo daily for 7 days or fewer before an invasive procedure. Imaging studies assessed treatment-emergent adverse events, including asymptomatic portal vein thrombosis. The primary end point was no requirement for platelet transfusion before the invasive procedure and rescue therapies for bleeding 7 days or fewer after the invasive procedure. RESULTS: The per-protocol population included 270 patients (95 with HCC). A significantly higher proportion of patients with HCC who received lusutrombopag achieved the primary end point (68.0%) vs patients who received placebo (8.9%) (P < .0001); in patients without HCC, these proportions were 77.0% vs 21.6% (P < .0001). Lusutrombopag reduced the need for platelet transfusions, increased platelet counts for 3 weeks, and reduced the number of bleeding events in patients with and without HCC compared with placebo. Risk of thrombosis was similar to that of placebo. CONCLUSIONS: Patients with and without HCC receiving lusutrombopag had a reduction in the number of platelet transfusions before invasive procedures compared with patients receiving placebo, with no increase in thrombosis or bleeding. L-PLUS 1: JapicCTI-132323; L-PLUS 2: ClinicalTrials.gov number no: NCT02389621.

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

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.

A randomized controlled trial of lusutrombopag in Japanese patients with chronic liver disease undergoing radiofrequency ablation.

BACKGROUND: Thrombocytopenia represents an obstacle for invasive procedures in chronic liver disease (CLD) patients. We aimed to estimate the appropriate dose and evaluate the efficacy and safety of lusutrombopag for the treatment of thrombocytopenia before percutaneous liver radiofrequency ablation (RFA) for primary hepatic cancer in patients with CLD. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study conducted in Japan, 61 CLD patients with platelet count < 50 × 103/µL at screening were randomized to placebo or lusutrombopag 2, 3, or 4 mg once daily for 7 days, followed by a 28-day post-treatment assessment period. The primary efficacy endpoint was the proportion of patients who did not require platelet transfusion before RFA. The pre-specified key secondary efficacy endpoint was the proportion of responders. Adverse events (AEs) and thrombosis-related AEs were evaluated. RESULTS: The proportion of patients who did not require platelet transfusion before RFA and that of responders were significantly higher (p < 0.01) in the 2-mg (80.0, 66.7%), 3-mg (81.3, 68.8%), and 4-mg groups (93.3, 80.0%) compared with the placebo group (20.0, 6.7%) and showed a dose-dependent effect. The incidence of AEs was 97.8 and 100% in the lusutrombopag (all groups) and placebo groups, respectively; no dose-related increase was observed. Four patients experienced thrombosis-related events (one each in the placebo and 2-mg groups, and two in the 4-mg group). A total of 16 (18%) adverse drug reactions occurred in the safety analysis set. CONCLUSIONS: Lusutrombopag 3 mg once daily for 7 days was effective without raising concerns about excessive increases in platelet count. CLINICAL TRIAL REGISTRATION: The study is registered at JapicCTI-121944.

An open-label, long-term, phase III extension trial of duloxetine in Japanese patients with fibromyalgia.

OBJECTIVES: We aimed to evaluate the long-term safety and efficacy of duloxetine 60 mg in Japanese patients with fibromyalgia enrolled from a preceding randomized, placebo-controlled, phase III duloxetine trial. METHODS: This was a long-term, open-label extension study. Patients received oral duloxetine once daily at a dose of 20 mg for 1 week, followed by 40 mg for 1 week, and then 60 mg for 48 weeks. The primary outcome was the frequency of adverse events (AEs) and adverse drug reactions (ADRs) of duloxetine. Efficacy and health outcomes were assessed. RESULTS: In total, 149 patients were enrolled from the preceding study. The median length of treatment was 364.0 days. The incidence of AEs and ADRs was 92.6 and 63.8%, respectively. ADRs occurring at an incidence of ≥5% were somnolence, constipation, nausea, weight increase, thirst, and malaise. The proportion of patients with mild, moderate, and severe AEs was 80.5, 10.1, and 2.0%. There were no serious treatment-related AEs in this study. The Brief Pain Inventory average pain score improved at all time-points compared with baseline (mean change ± standard deviation at Week 50 was -1.31 ± 1.70). CONCLUSIONS: Duloxetine was safe and effective in the long-term treatment of Japanese patients with fibromyalgia.

Randomized, Double-blind, Placebo-controlled Phase III Trial of Duloxetine Monotherapy in Japanese Patients With Chronic Low Back Pain.

STUDY DESIGN: A 14-week, randomized, double-blind, multicenter, placebo-controlled study of Japanese patients with chronic low back pain (CLBP) who were randomized to either duloxetine 60 mg once daily or placebo. OBJECTIVE: This study aimed to assess the efficacy and safety of duloxetine monotherapy in Japanese patients with CLBP. SUMMARY OF BACKGROUND DATA: In Japan, duloxetine is approved for the treatment of depression, diabetic neuropathic pain, and pain associated with fibromyalgia; however, no clinical study of duloxetine has been conducted for CLBP. METHODS: The primary efficacy measure was the change in the Brief Pain Inventory (BPI) average pain score from baseline to Week 14. Secondary efficacy measures included BPI pain (worst pain, least pain, pain right now), Patient's Global Impression of Improvement, Clinical Global Impressions of Severity, and Roland-Morris Disability Questionnaire, among other measures, and safety and tolerability. RESULTS: In total, 458 patients were randomized to receive either duloxetine (n = 232) or placebo (n = 226). The BPI average pain score improved significantly in the duloxetine group compared with that in the placebo group at Week 14 [-2.43 ±â€Š0.11 vs. -1.96 ±â€Š0.11, respectively; between-group difference (95% confidence interval), - 0.46 [-0.77 to-0.16]; P = 0.0026]. The duloxetine group showed significant improvement in many secondary measures compared with the placebo group, including BPI pain (least pain, pain right now) (between-group difference: -1.69 ±â€Š0.10, P = 0.0009; -2.42 ±â€Š0.12, P P = 0.0230, respectively), Patient's Global Impression of Improvement (2.46 ±â€Š0.07, P = 0.0026), Clinical Global Impressions of Severity (-1.46 ±â€Š0.06, P = 0.0019), and Roland-Morris Disability Questionnaire (-3.86 ±â€Š0.22, P = 0.0439). Adverse events occurring at a significantly higher incidence in the duloxetine group were somnolence, constipation, nausea, dizziness, and dry mouth, most of which were mild or moderate in severity and were resolved or improved. CONCLUSION: Duloxetine 60 mg was effective and well tolerated in Japanese CLBP patients. LEVEL OF EVIDENCE: 2.

A randomized, double-blind, placebo-controlled phase III trial of duloxetine in Japanese fibromyalgia patients.

INTRODUCTION: Fibromyalgia is characterized by widespread pain and is often accompanied by accessory symptoms. There are limited treatment options for this condition in Japan. Therefore, we conducted a phase III study to assess the efficacy and safety of duloxetine in Japanese patients with fibromyalgia. METHODS: This randomized, double-blind, placebo-controlled, parallel-group trial was conducted in Japan. Outpatients who met the American College of Rheumatology 1990 criteria for fibromyalgia and whose Brief Pain Inventory (BPI) average pain score was ≥4 were randomized to duloxetine 60 mg or placebo once daily for 14 weeks. The primary efficacy measure was the change in the BPI average pain score from baseline. Secondary efficacy, quality of life (QoL), and safety outcomes were also evaluated. Mixed-effects model repeated-measures (MMRM) analysis and last observation carried forward (LOCF) analysis of covariance were used to evaluate the primary efficacy measure. RESULTS: Overall, 393 patients were randomized to receive either duloxetine (n = 196) or placebo (n = 197). The MMRM analysis revealed no significant difference between duloxetine and placebo regarding the change in BPI average pain scores at week 14. Based on LOCF analysis, a statistically significant improvement in the change in BPI average pain scores at week 14 was observed for patients treated with duloxetine compared with placebo. Duloxetine treatment was associated with improved outcomes in nearly all secondary and post hoc analyses. The treatment was generally well tolerated. Somnolence, nausea, and constipation were the most common treatment-emergent adverse events in the duloxetine group. The discontinuation rates due to treatment-emergent adverse events were similar in both groups. CONCLUSIONS: Although the MMRM analysis did not demonstrate superiority of duloxetine over placebo, duloxetine treatment was associated with improved outcomes in secondary and post hoc analyses of the mean change in the BPI average pain score and most of the secondary outcomes, including analgesia and QoL. Duloxetine treatment was safe and well tolerated. These results suggest that duloxetine treatment could be associated with improvements in pain relief and QoL in Japanese patients with fibromyalgia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01552057 . Registered 9 March 2012.