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

Phase 3

Completed

• Conditions: Thrombocytopenia; Chronic Liver Disease
• Interventions: Drug: Placebo; Drug: Lusutrombopag

• Registration Number: NCT02389621
• Lead Sponsor: Shionogi

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.

Study Timeline

• Study First Submitted: 2015-03-10
• Study First Submitted QC: 2015-03-10
• Study First Posted: 2015-03-17
• Study Start: 2015-06-15
• Primary Completion: 2017-04-05
• Study Completion: 2017-04-19
• Disposition First Submitted: 2018-03-21
• Disposition First Submitted QC: 2018-03-21
• Disposition First Posted: 2018-03-23
• Results First Submitted: 2018-08-27
• Results First Submitted QC: 2018-08-27
• Results First Posted: 2018-09-25
• Status Verified: 2018-10
• Last Update Submitted: 2018-10-01
• Last Update Posted: 2018-10-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 215

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo once daily for up to 7 days.
Lusutrombopag	Lusutrombopag	Lusutrombopag 3 mg once daily for up to 7 days.

Primary Outcome Measures

Name	Time	Method
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	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Who Required no Platelet Transfusion During the Study	From Day 1 to end of the posttreatment period, 35 days.	Participants who did not undergo the invasive procedure were considered as having received platelet transfusion.
Duration of Increase in Platelet Count to ≥ 50 × 10⁹/L by Platelet Transfusion Status	From Day 1 to the end of the posttreatment period, 35 days.	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.
Number of Participants With Adverse Events (AEs)	From first dose of study drug to 28 days after the last dose, 35 days.
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).
Percentage of Participants Who Required Rescue Therapy for Bleeding During the Study	From Day 1 to the end of the possttreatment period, 35 days.	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.
Change From Baseline in Platelet Count Over Time	Baseline and Days 5, 6, 7, 8, 10, 12, 14, 17, 21, 28, and 35.
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).
Area Under the Plasma Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) 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).
Percentage of Participants With a Response	From Day 1 to the end of the posttreatment period, 35 days.	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	From Day 1 to the end of the posttreatment period, 35 days.	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.
Number of Participants With Specified Total Number of Platelet Transfusions	From Day 1 to the end of the posttreatment period, 35 days.	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.
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).