Chronic Liver DiseasePhase 3L-PLUS 2NCT02389621
Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
A Phase 3 study testing Lusutrombopag in people with Chronic Liver Disease and Thrombocytopenia, run by Shionogi.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Liver Disease, Thrombocytopenia
- What is being tested?
- Lusutrombopag
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 215 participants
- Where
- No sites listed yet
- Study dates
- 15 Jun 2015to 19 Apr 2017
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- Any of the following diseases:
- hematopoietic tumor
- aplastic anemia
- myelodysplastic syndrome
- myelofibrosis
- congenital thrombocytopenia
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- 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.
About this study
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)
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.
Read the 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.
- Conditions
- Chronic Liver Disease, Thrombocytopenia
- Being tested
- Lusutrombopag, Placebo
- Keywords
- Elective invasive procedures
- Medical subject headings
- Thrombocytopenia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LusutrombopagDrug
Also called S-888711
Tablets for oral administration
PlaceboDrug
Tablets for oral administration
| Study group | Role | What they receive |
|---|---|---|
| Lusutrombopag | Experimental | Lusutrombopag 3 mg once daily for up to 7 days. Receives: Drug: Lusutrombopag |
| Placebo | Placebo comparator | Placebo once daily for up to 7 days. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: From Randomization to 7 days after the invasive procedure, up to approximately 21 days.
Secondary outcomes (12)
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.
Measured: From Day 1 to end of the posttreatment period, 35 days.
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.
Measured: From Day 1 to the end of the posttreatment period, 35 days.
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.
Measured: From Day 1 to the end of the posttreatment period, 35 days.
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.
Measured: From Day 1 to the end of the posttreatment period, 35 days.
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.
Measured: From Day 1 to the end of the possttreatment period, 35 days.
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.
Measured: From Day 1 to the end of the posttreatment period, 35 days.
Change From Baseline in Platelet Count Over Time
Measured: Baseline and Days 5, 6, 7, 8, 10, 12, 14, 17, 21, 28, and 35.
Number of Participants With Adverse Events (AEs)
Measured: From first dose of study drug to 28 days after the last dose, 35 days.
Maximum Plasma Concentration (Cmax) of Lusutrombopag
Measured: 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).
Time to Maximum Plasma Concentration (Tmax) of Lusutrombopag
Measured: 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).
Area Under the Plasma Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for Lusutrombopag
Measured: 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).
Apparent Total Clearance (CL/F) of Lusutrombopag
Measured: 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).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Mar 2015 (estimated)
- Study start15 Jun 2015
- Primary completion5 Apr 2017
- Study completion19 Apr 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Chronic Liver DiseaseStudies of the same condition, open and under way.
- More trials run by ShionogiThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 215 participants (actual)
Sponsor and investigators
- Lead sponsor
- Shionogi
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Shionogi Clinical Trials Administrator Clinical Support Help Line, Study director, Shionogi
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02389621
- Sponsor's protocol ID
- 1423M0634
- Other IDs
- 2014-004942-91, 2014
- Acronym
- L-PLUS 2
- Status last verified
- Oct 2018
- First submitted
- 10 Mar 2015
- Last updated
- 30 Oct 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 35904722Alkhouri 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.
PubMed 32205226
Study at a glance
From the registry record, last updated by the sponsor on 30 Oct 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT02389621
- Acronym / sponsor ID
- L-PLUS 2 / 1423M0634
- Conditions
- Chronic Liver Disease, Thrombocytopenia
- Keywords
- Elective invasive procedures
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 215 participants (actual)
- Lead sponsor
- ShionogiIndustry (pharma, biotech, devices)
- Study start
- 15 Jun 2015 (actual)
- Primary completion
- 5 Apr 2017 (actual)
- Study completion
- 19 Apr 2017 (actual)
- First posted
- 17 Mar 2015 (estimated)
- Results
- Posted 25 Sep 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Lusutrombopag | Experimental | Drug: LusutrombopagLusutrombopag 3 mg once daily for up to 7 days. |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo once daily for up to 7 days. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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.
Key exclusion criteria (38 listed)
- Any of the following diseases:
- History of splenectomy.
- History of liver transplantation.
- Any of the following at Screening:
- Portal vein tumor embolism.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LusutrombopagAlso: S-888711Tablets for oral administration | Drug | Lusutrombopag |
| PlaceboTablets for oral administration | Drug | Placebo |
Primary outcome
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
Time frame: From Randomization to 7 days after the invasive procedure, up to approximately 21 days.
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.
12 secondary outcomes
Percentage of Participants Who Required no Platelet Transfusion During the Study
Time frame: From Day 1 to end of the posttreatment period, 35 days.
Percentage of Participants With a Response
Time frame: From Day 1 to the end of the posttreatment period, 35 days.
Duration of Increase in Platelet Count to ≥ 50 × 10⁹/L
Time frame: From Day 1 to the end of the posttreatment period, 35 days.
Duration of Increase in Platelet Count to ≥ 50 × 10⁹/L by Platelet Transfusion Status
Time frame: From Day 1 to the end of the posttreatment period, 35 days.
Percentage of Participants Who Required Rescue Therapy for Bleeding During the Study
Time frame: From Day 1 to the end of the possttreatment period, 35 days.
Number of Participants With Specified Total Number of Platelet Transfusions
Time frame: From Day 1 to the end of the posttreatment period, 35 days.
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.
Number of Participants With Adverse Events (AEs)
Time frame: From first dose of study drug to 28 days after the last dose, 35 days.
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).
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).
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).
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).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Oct 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 35904722Flamm 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.
- Derived from this study: PubMed 32205226Alkhouri 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Shionogi Clinical Trials Administrator Clinical Support Help Line study director
Shionogi
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Lusutrombopag in people with Chronic Liver Disease and Thrombocytopenia, run by Shionogi.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 38 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Oct 2018. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Sep 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 (time frame: From Randomization to 7 days after the invasive procedure, up to approximately 21 days.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02389621, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Oct 2018.