Efficacy & Additional Data
Mulpleo Clinical Trial Data and Post-Hoc Analysis
Mulpleo's efficacy has been proven across two randomised, double-blind, placebo-controlled trials: L-PLUS 11 and L-PLUS 24
Study design and pooled analysis
Mulpleo’s efficacy in reducing the need for platelet transfusions in chronic liver disease patients with severe thrombocytopenia undergoing invasive procedures has been proven across two randomised, double-blind, placebo-controlled studies: L-PLUS 1 and L-PLUS 22
Patients treated with Mulpleo also maintained platelet counts over ≥50x109/L for a median of 20.9 days for subjects not requiring a platelet transfusion, vs. 0.3 days for subjects requiring a platelet transfusion in the placebo group3
Patient population
Studies included 312 subjects with chronic liver disease (Child-Pugh class A and B), and platelet levels <50x109/L, undergoing scheduled invasive procedures in Japan (L-PLUS 1) and globally (L-PLUS 2).2,3
Randomisation
Patients randomised 1:1 to receive 3 mg/day Mulpleo or placebo oral tablets.2
Treatment duration before use of platelet transfusion
Mulpleo was administered orally for up to 7 days,* and administration of Mulpleo was stopped on day 5 to day 7 if the platelet count was ≥50x109/L together with an increase of ≥20x109/L from baseline.2
If patients in either group were found to have platelet levels <50x109/L immediately prior to the invasive procedure, a platelet transfusion was administered.2
*Please refer to the Mulpleo Summary of Product Characteristics for full posology information.2
Primary endpoints
L-PLUS 1: Proportion of patients who required no platelet transfusion prior to the primary invasive procedure.2
L-PLUS 2: Proportion of patients who required no platelet transfusion prior to the primary invasive procedure and no rescue therapy* for bleeding from randomisation through 7 days after the primary procedure.2
Pooled and individual study data shown: analyses per L-PLUS 2 primary outcome measure.
Study design3
Adapted from Brown RSet al. 20213
*Rescue therapy: Platelet preparations; other blood preparations, including red blood cells and plasma; volume expanders.4
Mulpleo demonstrated a significant reduction in the number of patients that needed a platelet transfusion prior to the primary invasive procedure and rescue therapy for bleeding vs. placebo2
Proportion of patients (intention to treat (ITT) population) who required no platelet transfusion* and no rescue therapy** (%; pooled primary endpoint)2
Adapted from Mulpleo (lusutrombopag) Summary of Product Characteristics.2
Pooled and individual study data: analyses per L-PLUS 2 primary outcome measures.
*Platelet transfusion was required if platelet count <50x109/L.2
**Rescue therapy: Platelet preparations; other blood preparations, including red blood cells and plasma; volume expanders5 from randomisation through 7 days after the primary invasive procedure.4
Mulpleo can help provide reliability for planned procedures, as platelet levels can be measured 2–4 days before the procedure and significantly fewer patients require platelet transfusion and rescue therapy vs. placebo.2
Almost 3x more Mulpleo patients did not require platelet transfusion prior to their procedure or rescue therapy following the procedure, vs. patients receiving placebo (p<0.0001)2
Significantly more patients treated with Mulpleo achieved a platelet count of ≥50x109/L vs. placebo (Secondary Endpoint)2
Proportion of patients (intention to treat population) achieving a platelet count of ≥50x109/L and minimum increase of 20x109/L from baseline (%)2
Adapted from Mulpleo (lusutrombopag) Summary of Product Characteristics.2
Pooled and individual study data: analyses per L-PLUS 2 primary outcome measures.
6x more patients receiving Mulpleo achieved a platelet count of ≥50x109/L and had a minimum increase of 20x109/L from baseline across two clinical trials vs. placebo (p<0.0001)2
Patients demonstrated a prolonged duration of effect with Mulpleo vs. placebo (Secondary Endpoint)3
Platelet counts in patients treated with Mulpleo without platelet transfusion vs. patients treated with placebo with platelet transfusion (pooled analysis)3
Adapted from Brown RS, et al. 2021.3
Pooled and individual study data: analyses per L-PLUS 2 primary outcome measures.
Mulpleo provides a median procedural window of approximately 3 weeks, allowing multiple procedures to be completed, if necessary.3
Across the two clinical trials, platelet counts remained at ≥50x109/L for a median of 20.9 days in patients treated with Mulpleo without platelet transfusion, vs. 0.3 days in patients treated with placebo with platelet transfusion3
Post-hoc analysis of platelet count increase
Patients treated with Mulpleo gained a clinically relevant increase in platelet count for nearly 3 weeks3
In a post hoc analysis of 2 Phase III clinical trials:3
Patients who received Mulpleo without platelet transfusion achieved a median platelet count ≥50x109L for 3 weeks3
Mulpleo in the real world
Data from real world practice supports the findings of the randomised controlled trials5-7.
Retrospective cohort study to compare the effect of Mulpleo and platelet transfusion
Retrospective cohort study to compare Mulpleo and platelet transfusion5
Study Design
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Study design |
Retrospective cohort study from Japanese DPC hospitals |
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Study objective |
To investigate and compare the effects of lusutrombopag and PT as prophylactic treatments to increase PCs in patients with CLD undergoing planned invasive procedures |
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Sample size |
1,990 patients (374 in the lusutrombopag group; 1,616 in the PT group) |
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Data Collection |
April 2008–May 2019 |
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Key inclusion criteria |
Patients with CLD Received ≥1 planned invasive procedure with administration of either Mulpleo or PT |
Endpoints
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Primary Objective |
Incidence of bleeding events during hospitalisation for invasive procedures |
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Secondary Objectives |
The incidence of rescue therapy for bleeding Mean medical costs – prophylactic and post-invasive LOS – total hospitalisation days and days from invasive procedure to discharge |
CLD, chronic liver disease; DPC, Diagnosis and Procedure Combination; LOS, length of stay; PC, platelet count; PT, platelet transfusion; SLD, severe liver disease.
Mulpleo reduced the number of bleeding events in a matched cohort study5
In a retrospective cohort study covering 11 years (April 2008 to May 2019), Mulpleo treatment led to fewer bleeding events and a lower requirement for rescue PT (n cases=379 per group) compared to PT.5
Significantly fewer bleeding events with Mulpleo vs PT (p<0.001)5
Fewer patients required rescue PT with Mulpleo vs PT (p<0.05)5,6
Furthermore, the subgroup analysis showed that the incidence of bleeding events was numerically lower in the Mulpleo group than in the PT group (3.2% vs. 5.1%); however, the difference was not statistically significant (p = 0.242).
PT, platelet transfusion. Bleeding events were defined by ICD-10 in Supplementary Material Table S5.
Mulpleo significantly reduced medical costs and LOS compared with PT5
Compared with PT, Mulpleo treatment was associated with lower medical costs and LOS in a retrospective RWE study including 758 patients5
Mean medical cost*
Length of stay
*Converted from JPY to GBP with £1 being equivalent to approximately ¥151.148 as of August 2021.
Median medical costs were calculated considering:
Prophylactic treatment costs: costs for prophylactic treatments to increase platelet counts, including those for Mulpleo prescribed within 30 days prior to the invasive procedure and PT prescribed at 1 day before and on the day of the invasive procedure.
Post-invasive procedure costs: total medical costs between the day of the invasive procedure and 30 days after the invasive procedure, excluding those for PT on the day of the invasive procedure.6
Repeated use of Mulpleo
Repeated use of Mulpleo is effective in raising platelets for patients with CLD6
Study Design
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Study design |
A retrospective single-centre study where Mulpleo was given in twice in 9 patients, 3 times in 3 patients, 5 times in 1 patient and 6 times in 1 patient. |
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Study objective |
To investigate the effect of Mulpleo readministration in patients with CLD and severe thrombocytopenia. |
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Sample size |
14 patients |
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Data Collection |
April 2016 – November 2020 |
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Key inclusion criteria |
Patients with CLD and either: severe thrombocytopenia (<50,000/µl), previous platelet counts of <50,000/µl, elongated prothrombin activity (70%) or deemed eligible by attending physician who were treated with Mulpleo at least twice. |
Endpoints
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Primary Objective |
Difference in platelet count between first, second and third or more treatments with Mulpleo |
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Secondary Objectives |
Number of platelet transfusions avoided by the Mulpleo group* Adverse events |
CLD, chronic liver disease; PC, platelet count.
Repeated use of Mulpleo shows no difference in terms of efficacy, time course, magnitude of platelet response or safety profile.6
Mean PC increase and rate of PC increase did not differ significantly with repeated Mulpleo treatment cycles6
There were no postoperative haemorrhagic complications, and no patient had an increase in platelet count >200,000/µl, which is a known risk factor for portal vein thrombosis.6
Appropriate measures such as discontinuation of lusutrombopag should be taken, if the platelet count reaches ≥50,000/µL as a result of a 20,000/µL increase from baseline.
There is limited information on the use of lusutrombopag in patients with severe (Child-Pugh class C) hepatic impairment. Lusutrombopag should only be used in such patients if the expected benefit outweighs the expected risks.
Repeated use of Mulpleo increases PC and is generally well tolerated6
Real life experience of Mulpleo for cirrhotic patients with thrombocytopenia
Real-world evidence shows that up to 84% of patients treated with Mulpleo do not require a platelet transfusion prior to an invasive procedure7
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of patients (n=21/25) treated with Mulpleo didn’t require a platelet transfusion prior to their invasive procedure.7 |
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Platelets >30x109/L at baseline of patients (n=16/17) treated with Mulpleo responded to treatment (platelet count ≥50x109/L).7 |
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Platelets ≤30x109/L at baseline of patients (n=5/8) treated with Mulpleo responded to treatment (platelet count ≥50x109/L).7 |
References
Hidaka H, et al. Clin Gastroenterol Hepatol. 2019;17:1192-1200
Mulpleo (lusutrombopag) Summary of Product Characteristics.
Brown RS, Imawari M, Izumi N, et al. JHEP Rep. 2021;3(2):100228.
Peck-Radosavljevic M, Simon K, Iacobellis A, et al. Hepatol. 2019;70(4):1336–1348.
Yoshida, et al. Poster presented at APASL Collaboration and Cure, 2021
Kawaratani H, et al. Hepatology Res 2020;50:1101–5.
Takada H, Kurosaki M, Nakanishi H, et al. PloS One. 2019;14(2):e0211122.