Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures

Thrombocytopenia Clinical Trial

— 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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02389621
• Other study ID #: 1423M0634
• Secondary ID: 2014-004942-91
• Status: Completed
• Phase: Phase 3
• Start date: June 15, 2015
• Est. completion date: April 19, 2017

Study information

• Verified date: October 2018
• Source: Shionogi Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 215
• Est. completion date: April 19, 2017
• Est. primary completion date: April 5, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Able to understand the study and comply with all study procedures.

2. Willing to provide written informed consent prior to Screening.

3. Male or female.

4. 18 years of age or older at the time of signing informed consent.

5. Platelet count < 50 × 10^9/L at baseline on Day 1 prior to randomization.

6. Undergoing an elective invasive procedure.

7. In the opinion of the investigator, able to meet study requirements.

8. 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.

9. 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:

1. 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.

2. History of splenectomy.

3. History of liver transplantation.

4. Any of the following at Screening:

• hepatic encephalopathy uncontrolled by drugs

• ascites uncontrolled by drugs.

5. Portal vein tumor embolism.

6. Known to be positive for the human immunodeficiency virus.

7. 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).

8. 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.

9. 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.

10. Absence of hepatopetal blood flow in the main trunk of the portal vein as demonstrated by Doppler ultrasonography within 28 days prior to randomization.

11. History or evidence of disease associated with a risk of bleeding (e.g., coagulation factor deficiency or von Willebrand factor deficiency).

12. Bleeding score at randomization = Grade 2 according to the World Health Organization (WHO) Bleeding Scale.

13. 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.

14. Any invasive procedure within 14 days prior to randomization.

15. Blood transfusion within 14 days prior to randomization.

16. Prior treatment with lusutrombopag (S-888711).

17. Pregnancy or lactation.

18. 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.

19. Considered ineligible by the investigator for any other reason.

Related Conditions & MeSH terms

• Chronic Liver Disease
• Liver Diseases
• Thrombocytopenia

Intervention

Drug:
• Lusutrombopag
Tablets for oral administration
• Placebo
Tablets for oral administration

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Shionogi

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	From Randomization to 7 days after the invasive procedure, up to approximately 21 days.
Secondary	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.	From Day 1 to end of the posttreatment period, 35 days.
Secondary	Percentage of Participants With a Response	A response was defined as a platelet count of = 50 × 10?/L with an increase of = 20 × 10?/L from Baseline at any time during the study. Participants who met this response criterion only after platelet transfusion were considered as nonresponders.	From Day 1 to the end of the posttreatment period, 35 days.
Secondary	Duration of Increase in Platelet Count to = 50 × 10?/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 × 10?/L.	From Day 1 to the end of the posttreatment period, 35 days.
Secondary	Duration of Increase in Platelet Count to = 50 × 10?/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 × 10?/L.	From Day 1 to the end of the posttreatment period, 35 days.
Secondary	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.	From Day 1 to the end of the possttreatment period, 35 days.
Secondary	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.	From Day 1 to the end of the posttreatment period, 35 days.
Secondary	Change From Baseline in Platelet Count Over Time		Baseline and Days 5, 6, 7, 8, 10, 12, 14, 17, 21, 28, and 35.
Secondary	Number of Participants With Adverse Events (AEs)		From first dose of study drug to 28 days after the last dose, 35 days.
Secondary	Maximum Plasma Concentration (Cmax) of Lusutrombopag		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).
Secondary	Time to Maximum Plasma Concentration (Tmax) of Lusutrombopag		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).
Secondary	Area Under the Plasma Concentration-time Curve Over the Dosing Interval t (AUC0-t) for Lusutrombopag		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).
Secondary	Apparent Total Clearance (CL/F) of Lusutrombopag		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).