L-PLUS 2: Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures

• Sponsor: Shionogi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02389621
• Collaborator: (none)
• Enrollment: 215
• Arms: 2
• Actual Duration (Months): 22.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Liver Disease; Thrombocytopenia	Drug: Lusutrombopag; Drug: Placebo	Phase 3

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

• Study Type: Interventional
• Actual Enrollment: 215 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: Jun 15, 2015
• Actual Primary Completion Date: Apr 5, 2017
• Actual Study Completion Date: Apr 19, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lusutrombopag Lusutrombopag 3 mg once daily for up to 7 days.	Drug: Lusutrombopag; Tablets for oral administration; Other Names: S-888711
Placebo Comparator: Placebo Placebo once daily for up to 7 days.	Drug: Placebo; Tablets for oral administration

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. Change From Baseline in Platelet Count Over Time [Baseline and Days 5, 6, 7, 8, 10, 12, 14, 17, 21, 28, and 35.]

8. Number of Participants With Adverse Events (AEs) [From first dose of study drug to 28 days after the last dose, 35 days.]

9. 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).]

10. 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).]

11. 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).]

12. 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).]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. History of splenectomy.

2. History of liver transplantation.

3. Any of the following at Screening:

• hepatic encephalopathy uncontrolled by drugs

• ascites uncontrolled by drugs.

1. Portal vein tumor embolism.

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

3. 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).

4. 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.

1. 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.

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

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

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

5. 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.

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

2. Blood transfusion within 14 days prior to randomization.

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

4. Pregnancy or lactation.

5. 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.

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Shionogi

Investigators

• Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line, Shionogi

Study Documents (Full-Text)

• Study Protocol - Feb 3, 2015
• Statistical Analysis Plan - Jun 5, 2017

More Information

Publications

None provided.

• Responsible Party: Shionogi
• ClinicalTrials.gov Identifier: NCT02389621
• Other Study ID Numbers: 1423M0634; 2014-004942-91
• First Posted: Mar 17, 2015
• Last Update Posted: Oct 30, 2018
• Last Verified: Oct 1, 2018

• Keywords provided by Shionogi: Elective invasive procedures
• Additional relevant MeSH terms: Liver Diseases; Thrombocytopenia

Study Results

Participant Flow

Recruitment Details	The study was conducted at 138 sites in 22 countries (Argentina, Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Hungary, Israel, Italy, Poland, Republic of Korea, Romania, Russian Federation, Spain, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, and United States of America).
Pre-assignment Detail	The study consisted of a screening period (up to 28 days), a treatment period of 7 days, and a posttreatment period (through 28 days posttreatment). Randomization was stratified by the primary invasive procedure (ie, liver ablation/coagulation or other invasive procedures) and baseline platelet count (< 35 × 10⁹/L or ≥ 35 × 10⁹/L).

Arm/Group Title	Lusutrombopag	Placebo
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days.	Placebo once daily for up to 7 days.
Period Title: Treatment Period
STARTED	108	107
Received Study Drug	107	107
COMPLETED	107	106
NOT COMPLETED	1	1
Period Title: Treatment Period
STARTED	107	106
COMPLETED	98	102
NOT COMPLETED	9	4

Baseline Characteristics

Arm/Group Title	Lusutrombopag	Placebo	Total
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days.	Placebo once daily for up to 7 days.	Total of all reporting groups
Overall Participants	108	107	215
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.2 (11.6)	56.1 (11.0)	55.7 (11.3)
Sex: Female, Male (Count of Participants)
Female	43 39.8%	38 35.5%	81 37.7%
Male	65 60.2%	69 64.5%	134 62.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	14 13%	12 11.2%	26 12.1%
Not Hispanic or Latino	93 86.1%	95 88.8%	188 87.4%
Unknown or Not Reported	1 0.9%	0 0%	1 0.5%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	2 1.9%	0 0%	2 0.9%
Asian	15 13.9%	17 15.9%	32 14.9%
Black or African American	1 0.9%	0 0%	1 0.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
White	85 78.7%	86 80.4%	171 79.5%
Other	3 2.8%	0 0%	3 1.4%
Not provided	2 1.9%	4 3.7%	6 2.8%
Planned Invasive Procedure (Count of Participants)
Liver ablation/ coagulation	7 6.5%	5 4.7%	12 5.6%
Other	101 93.5%	102 95.3%	203 94.4%
Baseline Platelet Count (Count of Participants)
< 35 × 10⁹/L	36 33.3%	38 35.5%	74 34.4%
≥ 35 × 10⁹/L	71 65.7%	68 63.6%	139 64.7%
Missing	1 0.9%	1 0.9%	2 0.9%

Outcome Measures

1. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

All randomized participants (intent-to-treat population)

Arm/Group Title	Lusutrombopag	Placebo
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days.	Placebo once daily for up to 7 days.
Measure Participants	108	107
Number (95% Confidence Interval) [percentage of participants]	64.8 60%	29.0 27.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lusutrombopag, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Statistical tests were performed at a 2-sided significance level of 0.05.
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted using the stratification factors of platelet count at randomization and the planned primary invasive procedure.
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	36.7
	Confidence Interval	(2-Sided) 95%; 24.9 to 48.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

All randomized participants (intent-to-treat population)

Arm/Group Title	Lusutrombopag	Placebo
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days.	Placebo once daily for up to 7 days.
Measure Participants	108	107
Number (95% Confidence Interval) [percentage of participants]	63.0 58.3%	29.0 27.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lusutrombopag, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	A gatekeeping procedure was employed for sequentially testing the prespecified important secondary endpoints, identified as the most clinically relevant endpoints. If the primary endpoint was statistically significant, the secondary endpoints were tested at the 0.05 level (2-sided) in sequence.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for the stratification factors of platelet count at randomization and the planned primary invasive procedure.
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	34.8
	Confidence Interval	(2-Sided) 95%; 22.8 to 46.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

All randomized participants (intent-to-treat population)

Arm/Group Title	Lusutrombopag	Placebo
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days.	Placebo once daily for up to 7 days.
Measure Participants	108	107
Number (95% Confidence Interval) [percentage of participants]	64.8 60%	13.1 12.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lusutrombopag, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	A gatekeeping procedure was employed for sequentially testing the prespecified important secondary endpoints, identified as the most clinically relevant endpoints. If the primary endpoint was statistically significant, the secondary endpoints were tested at the 0.05 level (2-sided) in sequence.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for the stratification factors of platelet count at randomization and the planned primary invasive procedure.
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	52.5
	Confidence Interval	(2-Sided) 95%; 42.0 to 62.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

All randomized participants with available data

Arm/Group Title	Lusutrombopag	Placebo
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days.	Placebo once daily for up to 7 days.
Measure Participants	107	107
Median (Inter-Quartile Range) [days]	15.11	0.98

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lusutrombopag, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	A gatekeeping procedure was employed for sequentially testing the prespecified important secondary endpoints, identified as the most clinically relevant endpoints. If the primary endpoint was statistically significant, the secondary endpoints were tested at the 0.05 level (2-sided) in sequence.
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	van Elteren test
	Comments	van Elteren test stratified by platelet transfusion during the study.

5. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

All randomized participants with available data

Arm/Group Title	Lusutrombopag With Platelet Transfusion	Lusutrombopag Without Platelet Transfusion	Placebo With Platelet Transfusion	Placebo Without Platelet Transfusion
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days in participants who received platelet transfusion.	Lusutrombopag 3 mg once daily for up to 7 days in participants who did not receive platelet transfusion.	Placebo once daily for up to 7 days in participants who received platelet transfusion.	Placebo once daily for up to 7 days in participants who did not receive platelet transfusion.
Measure Participants	34	73	73	34
Median (Inter-Quartile Range) [days]	1.73	19.21	0.00	8.86

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Placebo With Platelet Transfusion
	Comments
	Type of Statistical Test	Superiority
	Comments	A gatekeeping procedure was employed for sequentially testing the prespecified important secondary endpoints, identified as the most clinically relevant endpoints. If the primary endpoint was statistically significant, the secondary endpoints were tested at the 0.05 level (2-sided) in sequence.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon rank sum test
	Comments

6. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

All randomized participants (intent-to-treat population)

Arm/Group Title	Lusutrombopag	Placebo
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days.	Placebo once daily for up to 7 days.
Measure Participants	108	107
Number [percentage of participants]	0.0 0%	1.9 1.8%

7. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

All randomized participants (intent-to-treat population)

Arm/Group Title	Lusutrombopag	Placebo
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days.	Placebo once daily for up to 7 days.
Measure Participants	108	107
No transfusions	74 68.5%	34 31.8%
One transfusion	34 31.5%	61 57%
Two transfusions	0 0%	6 5.6%
Three transfusions	0 0%	5 4.7%
Four transfusions	0 0%	0 0%
Five transfusions	0 0%	1 0.9%

8. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

All randomized participants with available data at each time point.

Arm/Group Title	Lusutrombopag With Platelet Transfusion	Lusutrombopag Without Platelet Transfusion	Placebo With Platelet Transfusion	Placebo Without Platelet Transfusion
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days in participants who received platelet transfusion.	Lusutrombopag 3 mg once daily for up to 7 days in participants who did not receive platelet transfusion.	Placebo once daily for up to 7 days in participants who received platelet transfusion.	Placebo once daily for up to 7 days in participants who did not receive platelet transfusion.
Measure Participants	34	74	73	34
Day 5	1.1 (6.5)	10.4 (12.5)	0.4 (6.6)	6.1 (11.8)
Day 6	5.1 (8.1)	13.6 (15.7)	-0.6 (7.0)	6.7 (12.4)
Day 7	4.7 (7.9)	20.6 (16.8)	0.0 (7.7)	6.7 (12.9)
Day 8	7.7 (9.5)	27.4 (21.5)	-0.1 (5.2)	7.3 (13.5)
Day 10	12.6 (10.6)	36.7 (24.1)	2.1 (11.0)	12.7 (20.6)
Day 12	15.4 (12.3)	37.0 (18.5)	3.1 (9.5)	14.8 (24.0)
Day 14	17.3 (19.3)	33.5 (19.9)	4.0 (11.8)	12.8 (28.1)
Day 17	17.1 (23.4)	27.2 (21.1)	1.9 (9.0)	17.0 (27.7)
Day 21	9.8 (16.0)	20.9 (20.3)	2.5 (9.0)	13.2 (20.7)
Day 28	1.7 (11.4)	12.4 (18.8)	2.0 (8.9)	10.1 (17.6)
Day 35	-1.3 (6.2)	9.4 (19.3)	0.7 (9.1)	6.0 (15.9)

9. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of the study drug.

Arm/Group Title	Lusutrombopag	Placebo
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days.	Placebo once daily for up to 7 days.
Measure Participants	107	107
All adverse events	51 47.2%	52 48.6%
Serious adverse events	7 6.5%	7 6.5%
Adverse events with outcome of death	3 2.8%	0 0%
AEs leading to discontinuation of study drug	0 0%	1 0.9%
Treatment-related adverse events	6 5.6%	13 12.1%

10. Secondary Outcome

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).

Outcome Measure Data

Analysis Population Description

Participants in the intensive pharmacokinetic (PK) sampling group with at least 1 PK parameter estimated.

Arm/Group Title	Lusutrombopag
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days.
Measure Participants	9
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	157 (34.7)

11. Secondary Outcome

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).

Outcome Measure Data

Analysis Population Description

Participants in the intensive pharmacokinetic (PK) sampling group with at least 1 PK parameter estimated.

Arm/Group Title	Lusutrombopag
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days.
Measure Participants	9
Median (Full Range) [hours]	5.95

12. Secondary Outcome

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).

Outcome Measure Data

Analysis Population Description

Participants in the intensive pharmacokinetic (PK) sampling group with at least 1 PK parameter estimated.

Arm/Group Title	Lusutrombopag
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days.
Measure Participants	9
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	2737 (36.1)

13. Secondary Outcome

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).

Outcome Measure Data

Analysis Population Description

Participants in the intensive pharmacokinetic (PK) sampling group with at least 1 PK parameter estimated.

Arm/Group Title	Lusutrombopag
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days.
Measure Participants	9
Geometric Mean (Geometric Coefficient of Variation) [L/h]	1.10 (36.1)

Adverse Events

Time Frame	From first dose of study drug until 28 days after last dose, 35 days
Arm/Group Title	Lusutrombopag		Placebo
Arm/Group Description	Lusutrombopag 3 mg once daily for up to 7 days.		Placebo once daily for up to 7 days.
All Cause Mortality
	Lusutrombopag		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/107 (2.8%)		0/107 (0%)
Serious Adverse Events
	Lusutrombopag		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/107 (6.5%)		7/107 (6.5%)
Blood and lymphatic system disorders
Anemia	1/107 (0.9%)		0/107 (0%)
Cardiac disorders
Cardiac arrest	1/107 (0.9%)		0/107 (0%)
Cardiac ventricular thrombosis	1/107 (0.9%)		0/107 (0%)
Gastrointestinal disorders
Abdominal pain lower	1/107 (0.9%)		0/107 (0%)
Nausea	0/107 (0%)		1/107 (0.9%)
Vomiting	0/107 (0%)		1/107 (0.9%)
General disorders
Multiorgan failure	1/107 (0.9%)		0/107 (0%)
Hepatobiliary disorders
Hepatic cirrhosis	1/107 (0.9%)		0/107 (0%)
Portal vein thrombosis	1/107 (0.9%)		0/107 (0%)
Metabolism and nutrition disorders
Dehydration	0/107 (0%)		1/107 (0.9%)
Fluid retention	1/107 (0.9%)		0/107 (0%)
Hypokalemia	0/107 (0%)		1/107 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma	0/107 (0%)		2/107 (1.9%)
Nervous system disorders
Hepatic encephalopathy	1/107 (0.9%)		2/107 (1.9%)
Encephalopathy	0/107 (0%)		1/107 (0.9%)
Renal and urinary disorders
Acute kidney injury	1/107 (0.9%)		0/107 (0%)
Vascular disorders
Circulatory collapse	0/107 (0%)		1/107 (0.9%)
Hypertensive crisis	0/107 (0%)		1/107 (0.9%)
Vessel perforation	1/107 (0.9%)		0/107 (0%)
Other (Not Including Serious) Adverse Events
	Lusutrombopag		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/107 (21.5%)		22/107 (20.6%)
Gastrointestinal disorders
Abdominal pain	5/107 (4.7%)		5/107 (4.7%)
Nausea	2/107 (1.9%)		4/107 (3.7%)
Abdominal pain upper	2/107 (1.9%)		3/107 (2.8%)
Ascites	2/107 (1.9%)		3/107 (2.8%)
Diarrhea	3/107 (2.8%)		2/107 (1.9%)
General disorders
Fatigue	3/107 (2.8%)		7/107 (6.5%)
Edema peripheral	3/107 (2.8%)		4/107 (3.7%)
Pyrexia	3/107 (2.8%)		2/107 (1.9%)
Infections and infestations
Nasopharyngitis	3/107 (2.8%)		0/107 (0%)
Injury, poisoning and procedural complications
Procedural pain	3/107 (2.8%)		2/107 (1.9%)
Nervous system disorders
Headache	6/107 (5.6%)		2/107 (1.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor can embargo results from a PI's center until the combined results from the completed study have been published in full or the sponsor confirms there will be no multicenter study publication. Results communications must be provided to the sponsor for review at least 60 days before submission for publication. By written request, the sponsor can extend the embargo up to an additional 60 days. The sponsor cannot require changes to scientific content and cannot further extend the embargo.