Back to resultsSafety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures (L-PLUS 2)
Primary Purpose
Chronic Liver Disease, Thrombocytopenia
Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Lusutrombopag
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Chronic Liver Disease focused on measuring Elective invasive procedures
Eligibility Criteria
Inclusion Criteria:
- Able to understand the study and comply with all study procedures.
- Willing to provide written informed consent prior to Screening.
- Male or female.
- 18 years of age or older at the time of signing informed consent.
- Platelet count < 50 × 10^9/L at baseline on Day 1 prior to randomization.
- Undergoing an elective invasive procedure.
- In the opinion of the investigator, able to meet study requirements.
- Male patients who are sterile or who agree to use an appropriate method of contraception (including use of a condom with spermicide) from Screening to completion of the Post-treatment Period.
- Female patients who are not postmenopausal or surgically sterile need to agree to use a highly effective contraception (including contraceptive implant, injectable contraceptive, combination hormonal contraceptive [including vaginal rings], intrauterine contraceptive device or vasectomised partner) from Screening to completion of the Post-treatment Period. Barrier method with or without spermicide, double barrier contraception and oral contraceptive pill are insufficient methods on their own.
Exclusion Criteria:
Any of the following diseases:
- hematopoietic tumor
- aplastic anemia
- myelodysplastic syndrome
- myelofibrosis
- congenital thrombocytopenia
- drug-induced thrombocytopenia
- generalized infection requiring treatment except for viral liver disease
- immune thrombocytopenia.
- History of splenectomy.
- History of liver transplantation.
Any of the following at Screening:
- hepatic encephalopathy uncontrolled by drugs
- ascites uncontrolled by drugs.
- Portal vein tumor embolism.
- Known to be positive for the human immunodeficiency virus.
- Past or present thrombosis or prothrombotic condition (e.g., cerebral infarction, myocardial infarction, angina pectoris, coronary artery stent placement, angioplasty, coronary artery bypass grafting, congestive heart failure [New York Heart Association Grade III/IV], arrhythmia known to increase the risk of thromboembolic events [atrial fibrillation], pulmonary thromboembolism, deep vein thrombosis, or disseminated intravascular coagulation syndrome).
History or evidence of any of the following diseases:
- congenital thrombotic disease (eg, antithrombin deficiency, protein C deficiency, protein S deficiency, or coagulation factor [Factor V Leiden] mutation)
- acquired thrombotic disease (eg, antiphospholipid antibody syndrome, paroxysmal nocturnal hemoglobinuria, hyperhomocysteinemia, or increased factor VIII)
- Budd Chiari syndrome.
- Portal vein thrombosis based on ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) within 28 days prior to randomization or a history of portal vein thrombosis.
- Absence of hepatopetal blood flow in the main trunk of the portal vein as demonstrated by Doppler ultrasonography within 28 days prior to randomization.
- History or evidence of disease associated with a risk of bleeding (e.g., coagulation factor deficiency or von Willebrand factor deficiency).
- Bleeding score at randomization ≥ Grade 2 according to the World Health Organization (WHO) Bleeding Scale.
Any of the following drugs or therapies within 90 days prior to randomization:
- anticancer drugs
- interferon preparations
- radiation therapy
- exsanguination
- other thrombopoietin receptor agonist
- any investigational agent.
- Any invasive procedure within 14 days prior to randomization.
- Blood transfusion within 14 days prior to randomization.
- Prior treatment with lusutrombopag (S-888711).
- Pregnancy or lactation.
- Known or suspected ongoing, active alcohol or substance abuse. Patients with a recent history who the investigator feels are able to comply with the study procedures and medications will be allowed to participate.
- Considered ineligible by the investigator for any other reason.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Lusutrombopag
Placebo
Arm Description
Lusutrombopag 3 mg once daily for up to 7 days.
Placebo once daily for up to 7 days.
Outcomes
Primary Outcome Measures
Percentage of Participants Who Required No Platelet Transfusion Prior to the Primary Invasive Procedure and No Rescue Therapy For Bleeding From Randomization Through 7 Days After the Primary Elective Procedure
Participants were considered as meeting the primary endpoint if all of the following conditions were satisfied:
Required no platelet transfusion from the date of randomization through at least 7 days after the primary invasive procedure
Did not receive the following rescue therapy for bleeding from the date of randomization through 7 days after the primary invasive procedure
Platelet preparations
Other blood preparations, including red blood cells and plasma
Volume expanders
Underwent an invasive procedure. Participants who received at least one platelet transfusion prior to the primary invasive procedure, received at least one rescue therapy for bleeding from the date of randomization through 7 days after the primary invasive procedure, discontinued from the study before undergoing the primary invasive procedure, or did not undergo an invasive procedure were considered as not meeting the primary endpoint.
Secondary Outcome Measures
Percentage of Participants Who Required no Platelet Transfusion During the Study
Participants who did not undergo the invasive procedure were considered as having received platelet transfusion.
Percentage of Participants With a Response
A response was defined as a platelet count of ≥ 50 × 10⁹/L with an increase of ≥ 20 × 10⁹/L from Baseline at any time during the study. Participants who met this response criterion only after platelet transfusion were considered as nonresponders.
Duration of Increase in Platelet Count to ≥ 50 × 10⁹/L
The duration of the increase in platelet count was defined as the number of days during which the platelet count was maintained as ≥ 50 × 10⁹/L.
Duration of Increase in Platelet Count to ≥ 50 × 10⁹/L by Platelet Transfusion Status
The duration of the increase in platelet count was defined as the number of days during which the platelet count was maintained as ≥ 50 × 10⁹/L.
Percentage of Participants Who Required Rescue Therapy for Bleeding During the Study
Participants who received rescue therapy for bleeding events during the study. Platelet preparations, other blood preparations (including red blood cells and plasma), and volume expanders were considered as rescue therapy for bleeding events.
Number of Participants With Specified Total Number of Platelet Transfusions
The number of transfusions administered to each patient were collected over the duration of the trial. The data are presented as the number of patients with the highest total number of transfusions followed by the next highest number of transfusions, etc.
Change From Baseline in Platelet Count Over Time
Number of Participants With Adverse Events (AEs)
Maximum Plasma Concentration (Cmax) of Lusutrombopag
Time to Maximum Plasma Concentration (Tmax) of Lusutrombopag
Area Under the Plasma Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for Lusutrombopag
Apparent Total Clearance (CL/F) of Lusutrombopag
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02389621
Brief Title
Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
Acronym
L-PLUS 2
Official Title
A Phase 3 Randomised, Double-blind, Placebo-controlled Study to Assess the Safety and Efficacy of S-888711 (Lusutrombopag) for the Treatment of Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures (L-PLUS 2)
Study Type
Interventional
2. Study Status
Record Verification Date
October 2018
Overall Recruitment Status
Completed
Study Start Date
June 15, 2015 (Actual)
Primary Completion Date
April 5, 2017 (Actual)
Study Completion Date
April 19, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shionogi
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The primary purpose of this study is to compare the efficacy of lusutrombopag with placebo for the treatment of thrombocytopenia in patients with chronic liver disease who are undergoing elective invasive procedures.
Detailed Description
The study consists of 3 periods: a screening period (up to 28 days prior to randomization), a treatment period of 7 days (Days 1 to 7 during which study drug is to be administered for 4 to 7 days), and a posttreatment period (through 28 days posttreatment).
Once-daily treatment with lusutrombopag 3 mg or placebo is to commence on Day 1 and continue for up to 7 days. Platelet count is to be determined on Days 5, 6, and 7 prior to administration of study drug; if a participant meets the administration stopping criterion (ie, platelet count ≥ 50 × 10⁹/L with an increase of ≥ 20 × 10⁹/L from baseline), no additional dose of study drug is to be administered. The planned invasive procedure is to be performed in the posttreatment period between Days 9 and 14. Platelet count for determination of the need for platelet transfusion is to be determined on or after Day 8, but no more than 2 days prior to the invasive procedure; a platelet transfusion is required if the platelet count is < 50 × 10⁹/L.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Liver Disease, Thrombocytopenia
Keywords
Elective invasive procedures
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
215 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Lusutrombopag
Arm Type
Experimental
Arm Description
Lusutrombopag 3 mg once daily for up to 7 days.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo once daily for up to 7 days.
Intervention Type
Drug
Intervention Name(s)
Lusutrombopag
Other Intervention Name(s)
S-888711
Intervention Description
Tablets for oral administration
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Tablets for oral administration
Primary Outcome Measure Information:
Title
Percentage of Participants Who Required No Platelet Transfusion Prior to the Primary Invasive Procedure and No Rescue Therapy For Bleeding From Randomization Through 7 Days After the Primary Elective Procedure
Description
Participants were considered as meeting the primary endpoint if all of the following conditions were satisfied:
Required no platelet transfusion from the date of randomization through at least 7 days after the primary invasive procedure
Did not receive the following rescue therapy for bleeding from the date of randomization through 7 days after the primary invasive procedure
Platelet preparations
Other blood preparations, including red blood cells and plasma
Volume expanders
Underwent an invasive procedure. Participants who received at least one platelet transfusion prior to the primary invasive procedure, received at least one rescue therapy for bleeding from the date of randomization through 7 days after the primary invasive procedure, discontinued from the study before undergoing the primary invasive procedure, or did not undergo an invasive procedure were considered as not meeting the primary endpoint.
Time Frame
From Randomization to 7 days after the invasive procedure, up to approximately 21 days.
Secondary Outcome Measure Information:
Title
Percentage of Participants Who Required no Platelet Transfusion During the Study
Description
Participants who did not undergo the invasive procedure were considered as having received platelet transfusion.
Time Frame
From Day 1 to end of the posttreatment period, 35 days.
Title
Percentage of Participants With a Response
Description
A response was defined as a platelet count of ≥ 50 × 10⁹/L with an increase of ≥ 20 × 10⁹/L from Baseline at any time during the study. Participants who met this response criterion only after platelet transfusion were considered as nonresponders.
Time Frame
From Day 1 to the end of the posttreatment period, 35 days.
Title
Duration of Increase in Platelet Count to ≥ 50 × 10⁹/L
Description
The duration of the increase in platelet count was defined as the number of days during which the platelet count was maintained as ≥ 50 × 10⁹/L.
Time Frame
From Day 1 to the end of the posttreatment period, 35 days.
Title
Duration of Increase in Platelet Count to ≥ 50 × 10⁹/L by Platelet Transfusion Status
Description
The duration of the increase in platelet count was defined as the number of days during which the platelet count was maintained as ≥ 50 × 10⁹/L.
Time Frame
From Day 1 to the end of the posttreatment period, 35 days.
Title
Percentage of Participants Who Required Rescue Therapy for Bleeding During the Study
Description
Participants who received rescue therapy for bleeding events during the study. Platelet preparations, other blood preparations (including red blood cells and plasma), and volume expanders were considered as rescue therapy for bleeding events.
Time Frame
From Day 1 to the end of the possttreatment period, 35 days.
Title
Number of Participants With Specified Total Number of Platelet Transfusions
Description
The number of transfusions administered to each patient were collected over the duration of the trial. The data are presented as the number of patients with the highest total number of transfusions followed by the next highest number of transfusions, etc.
Time Frame
From Day 1 to the end of the posttreatment period, 35 days.
Title
Change From Baseline in Platelet Count Over Time
Time Frame
Baseline and Days 5, 6, 7, 8, 10, 12, 14, 17, 21, 28, and 35.
Title
Number of Participants With Adverse Events (AEs)
Time Frame
From first dose of study drug to 28 days after the last dose, 35 days.
Title
Maximum Plasma Concentration (Cmax) of Lusutrombopag
Time Frame
Day 5, predose and 2, 4, 6, 8, 24, and 48 hours post-dose (24 and 48 hours post-dose = Day 6 and Day 7 prior to dose on that day).
Title
Time to Maximum Plasma Concentration (Tmax) of Lusutrombopag
Time Frame
Day 5, predose and 2, 4, 6, 8, 24, and 48 hours post-dose (24 and 48 hours post-dose = Day 6 and Day 7 prior to dose on that day).
Title
Area Under the Plasma Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for Lusutrombopag
Time Frame
Day 5, predose and 2, 4, 6, 8, 24, and 48 hours post-dose (24 and 48 hours post-dose = Day 6 and Day 7 prior to dose on that day).
Title
Apparent Total Clearance (CL/F) of Lusutrombopag
Time Frame
Day 5, predose and 2, 4, 6, 8, 24, and 48 hours post-dose (24 and 48 hours post-dose = Day 6 and Day 7 prior to dose on that day).
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Able to understand the study and comply with all study procedures.
Willing to provide written informed consent prior to Screening.
Male or female.
18 years of age or older at the time of signing informed consent.
Platelet count < 50 × 10^9/L at baseline on Day 1 prior to randomization.
Undergoing an elective invasive procedure.
In the opinion of the investigator, able to meet study requirements.
Male patients who are sterile or who agree to use an appropriate method of contraception (including use of a condom with spermicide) from Screening to completion of the Post-treatment Period.
Female patients who are not postmenopausal or surgically sterile need to agree to use a highly effective contraception (including contraceptive implant, injectable contraceptive, combination hormonal contraceptive [including vaginal rings], intrauterine contraceptive device or vasectomised partner) from Screening to completion of the Post-treatment Period. Barrier method with or without spermicide, double barrier contraception and oral contraceptive pill are insufficient methods on their own.
Exclusion Criteria:
Any of the following diseases:
hematopoietic tumor
aplastic anemia
myelodysplastic syndrome
myelofibrosis
congenital thrombocytopenia
drug-induced thrombocytopenia
generalized infection requiring treatment except for viral liver disease
immune thrombocytopenia.
History of splenectomy.
History of liver transplantation.
Any of the following at Screening:
hepatic encephalopathy uncontrolled by drugs
ascites uncontrolled by drugs.
Portal vein tumor embolism.
Known to be positive for the human immunodeficiency virus.
Past or present thrombosis or prothrombotic condition (e.g., cerebral infarction, myocardial infarction, angina pectoris, coronary artery stent placement, angioplasty, coronary artery bypass grafting, congestive heart failure [New York Heart Association Grade III/IV], arrhythmia known to increase the risk of thromboembolic events [atrial fibrillation], pulmonary thromboembolism, deep vein thrombosis, or disseminated intravascular coagulation syndrome).
History or evidence of any of the following diseases:
congenital thrombotic disease (eg, antithrombin deficiency, protein C deficiency, protein S deficiency, or coagulation factor [Factor V Leiden] mutation)
acquired thrombotic disease (eg, antiphospholipid antibody syndrome, paroxysmal nocturnal hemoglobinuria, hyperhomocysteinemia, or increased factor VIII)
Budd Chiari syndrome.
Portal vein thrombosis based on ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) within 28 days prior to randomization or a history of portal vein thrombosis.
Absence of hepatopetal blood flow in the main trunk of the portal vein as demonstrated by Doppler ultrasonography within 28 days prior to randomization.
History or evidence of disease associated with a risk of bleeding (e.g., coagulation factor deficiency or von Willebrand factor deficiency).
Bleeding score at randomization ≥ Grade 2 according to the World Health Organization (WHO) Bleeding Scale.
Any of the following drugs or therapies within 90 days prior to randomization:
anticancer drugs
interferon preparations
radiation therapy
exsanguination
other thrombopoietin receptor agonist
any investigational agent.
Any invasive procedure within 14 days prior to randomization.
Blood transfusion within 14 days prior to randomization.
Prior treatment with lusutrombopag (S-888711).
Pregnancy or lactation.
Known or suspected ongoing, active alcohol or substance abuse. Patients with a recent history who the investigator feels are able to comply with the study procedures and medications will be allowed to participate.
Considered ineligible by the investigator for any other reason.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Shionogi Clinical Trials Administrator Clinical Support Help Line
Organizational Affiliation
Shionogi
Official's Role
Study Director
12. IPD Sharing Statement
Citations:
PubMed Identifier
35904722
Citation
Flamm SL, Peck-Radosavljevic M, Fukuhara T, Bentley R, Katsube T, Ochiai T, Kano T, Tsukimura E, Sasaki R, Osaki Y. Pharmacokinetic Assessment and Treatment Effect of Lusutrombopag in Child-Pugh Class C Patients: Review of Patient Data from Two Clinical Studies and Post-Marketing Surveillance. Adv Ther. 2022 Sep;39(9):4285-4298. doi: 10.1007/s12325-022-02237-8. Epub 2022 Jul 29.
Results Reference
derived
PubMed Identifier
32205226
Citation
Alkhouri N, Imawari M, Izumi N, Osaki Y, Ochiai T, Kano T, Bentley R, Trevisani F. Lusutrombopag Is Safe and Efficacious for Treatment of Thrombocytopenia in Patients With and Without Hepatocellular Carcinoma. Clin Gastroenterol Hepatol. 2020 Oct;18(11):2600-2608.e1. doi: 10.1016/j.cgh.2020.03.032. Epub 2020 Mar 20.
Results Reference
derived
Learn more about this trial
Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
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