A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Once-daily Oral Avatrombopag in Japanese Subjects With Chronic Liver Diseases and Thrombocytopenia

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Once-daily Oral Avatrombopag in Japanese Subjects With Chronic Liver Disease and Thrombocytopenia

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02227693

Enrollment

Registered

2014-08-28

Start date

2014-07-31

Completion date

2015-04-01

Last updated

2019-02-28

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Thrombocytopenia Associated With Chronic Liver Disease

Keywords

Thrombocytopenia, Chronic Liver Disease

Brief summary

This is a phase 2, randomized, double-blind, placebo-controlled, parallel group study using avatrombopag for Japanese subjects with thrombocytopenia associated with chronic liver disease. This study will assess the effect of avatrombopag on platelet counts in Japanese subjects. Subjects will be enrolled into 2 cohorts according to the mean platelet count measured at Screening and Baseline. Within the lower baseline platelet count cohort (less than 40 x 10\^9/L), subjects will be randomized in a 1:1:1:3 ratio to receive placebo, 20 mg avatrombopag, 40 mg avatrombopag, or 60 mg avatrombopag for 5 days. Within the higher baseline platelet count cohort (from 40 to less than 50 x 10\^9/L), subjects will be randomized in a 2:1:2 ratio to receive placebo, 20 mg avatrombopag, or 40 mg avatrombopag for 5 days.

Detailed description

This study will consist of Prerandomization Phase and Randomization Phase. The Prerandomization Phase includes a Screening Period (Day -28 to Day -1) and a Baseline Period (Day 1). During the Prerandomization Phase, participants will be divided into two cohorts based on the platelet count: Low Platelet Count Cohort and High Platelet Count Cohort. Participants in Low Platelet Count Cohort will be randomized to receive one of the four treatments: Placebo, Avatrombopag 20 mg, Avatrombopag 40 mg, or Avatrombopag 60 mg. Participants in High Platelet Count Cohort will be randomized to receive one of the three treatments: Placebo, Avatrombopag 20 mg, or Avatrombopag 40 mg. The Randomization Phase includes the Treatment Period and the Follow-up Period. The Follow-up Period comprises 3 visits: Visit 4 (5 to 8 days after last dose of study drug \[Study Day 10 to 13\]), Visit 5 (12 to 15 days after last dose of study drug \[Study Day 17 to 20\]), and 30 days after receiving the last dose of study drug.

Interventions

DRUGavatrombopag

E5501 (avatrombopag) 20-mg tablets

DRUGPlacebo

Placebo matching 20-mg tablets

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

20 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Japanese subjects greater than or equal to 20 years of age at Screening with chronic liver disease. 2. Subjects who have a mean baseline platelet count of less than 50 x 10\^9/L. Platelet counts will be measured on 2 separate occasions, during the Screening Period and at Baseline, and must be performed at least one day apart with neither platelet count greater than 60 x 10\^9/L. 3. Model For End-stage Liver Disease (MELD) score 24 at Screening. 4. If taking inhibitors of P glycoprotein (P-gp), except for verapamil, dose must be stable for 7 days prior to Screening. 5. Provide written informed consent. 6. Willing and able to comply with all aspects of the protocol.

Exclusion criteria

1. Any history of arterial or venous thrombosis, including partial or complete thrombosis. 2. Evidence of thrombosis (partial or complete) in the main portal vein, portal vein branches, or any part of the splenic mesenteric system at Screening. 3. Portal vein blood flow velocity rate less than 10 cm/second at Screening. 4. Hepatic encephalopathy that cannot be effectively treated. 5. Subjects with HCC with Barcelona Clinic Liver Cancer (BCLC) staging classification C or D. 6. Platelet transfusion or receipt of blood products containing platelets within 7 days of Screening. However packed red blood cells are permitted. 7. Heparin, warfarin, nonsteroidal anti-inflammatory drugs (NSAID), aspirin, verapamil, and antiplatelet therapy with ticlopidine or glycoprotein IIb/IIIa antagonists (eg, tirofiban) within 7 days of Screening. 8. Use of erythropoietin stimulating agents within 7 days of Screening. 9. Interferon (IFN) use within 14 days of Screening. 10. Estrogen-containing hormonal contraceptive or hormone replacement therapy use within 30 days of Screening. 11. Active infection requiring systemic antibiotic therapy within 7 days of Screening. However, prophylactic use of antibiotics is permitted. 12. Alcohol abuse, alcohol dependence syndrome, drug abuse, or drug dependence within 6 months of the study start (unless participating in a controlled rehabilitation program) or acute alcoholic hepatitis (chronic alcoholic hepatitis is allowed) within 6 months of the study start. 13. Known to be human immunodeficiency virus positive. 14. Any clinically significant acute or active bleeding (eg, gastrointestinal, central nervous system). 15. Known history of any primary hematologic disorder (eg, immune thrombocytopenic purpura, myelodysplastic syndrome). 16. Known medical history of genetic prothrombotic syndromes (eg, Factor V Leiden; prothrombin G20210A; ATIII deficiency etc.) 17. Subjects with a history of significant cardiovascular disease (eg, congestive heart failure New York Heart Association Grade III/IV, arrhythmia known to increase the risk of thromboembolic events \[eg, atrial fibrillation\], coronary artery stent placement, angioplasty, and coronary artery bypass grafting). 18. Females of childbearing potential who have had unprotected sexual intercourse within 30 days before study entry and who do not agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier method \[such as condom plus diaphragm with spermicide\], a progesterone only contraceptive implant/injection, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the subject must agree to use a double barrier method as described above if she becomes sexually active during the study period or for 30 days after study drug discontinuation. All females will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrhea in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) at least 1 month before dosing. 19. Females who are lactating or pregnant at Screening or Baseline (as documented by a positive serum beta-human chorionic gonadotropin \[B-hCG\] test with a minimum sensitivity 25 IU/L or equivalent units of B-hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. 20. Post liver transplant subjects. 21. Any subject who has previously received avatrombopag. 22. Hypersensitivity to avatrombopag maleate or any of its excipients. 23. Hemoglobin levels less than or equal to 8.0 or greater than or equal to 16.0 g/dL at Screening. 24. White blood cell count less than or equal to 1.5 x 10\^9/L or greater than or equal to 15.0 x 10\^9/L at Screening. 25. Serum sodium level less than or equal to 130 milliequivalents/L at Screening. 26. Current malignancy including solid tumors and hematologic malignancies (except HCC). 27. Any history of a medical condition or a concomitant medical condition that, in the opinion of the investigator(s), would compromise the subject's ability to safely complete the study. 28. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days of Screening.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L and at Least 20 x 10^9/L Increase From Baseline at Visit 4	Baseline and Visit 4 (Day 10)	Responders were defined as participants whose platelet count was greater than or equal to 50×10\^9/liter (L) and change from baseline was at least 20×10\^9/L at Visit 4. Participants receiving a platelet transfusion prior to the platelet count assessment at Visit 4 were considered as non-responders in the analysis. Two-sided 95% confidence interval (CI) is calculated by Clopper and Pearson method.

Secondary

Measure	Time frame	Description
Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 3 (Day 4 or 5), Visit 4 (Day 10), Visit 5 (Day 17) and Visit 6 (Day 35)	Responders were defined as the participants whose platelet count greater than or equal to 75 x 10\^9/L by visit. Participants receiving a platelet transfusion prior to the platelet count assessment at Visit 4 were considered as non-responders in the analysis. Two-sided 95% CI is calculated by Clopper and Pearson method.
Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 3 (Day 4 or 5), Visit 4 (Day 10), Visit 5 (Day 17) and Visit 6 (Day 35)	Responders were defined as the participants whose platelet count greater than or equal to 150 x 10\^9/L by visit. Participants receiving a platelet transfusion prior to the platelet count assessment at Visit 4 were considered as non-responders in the analysis.
Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 3 (Day 4 or 5), Visit 4 (Day 10), Visit 5 (Day 17) and Visit 6 (Day 35)	Responders were defined as the participants whose platelet count greater than or equal to 200 x 10\^9/L by visit. Participants receiving a platelet transfusion prior to the platelet count assessment at Visit 4 were considered as non-responders in the analysis.
Platelet Count and Change From Baseline in Platelet Count by Visit	Baseline, Visit 3 (Day 4 or 5), Visit 4 (Day 10), Visit 5 (Day 17) and Visit 6 (Day 35)	—
Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 3 (Day 4 or 5), Visit 4 (Day 10), Visit 5 (Day 17) and Visit 6 (Day 35)	Responders were defined as the participants whose platelet count greater than or equal to 50 x 10\^9/L by visit. Participants receiving a platelet transfusion prior to the platelet count assessment at Visit 4 were considered as non-responders in the analysis. Two-sided 95% CI is calculated by Clopper and Pearson method.

Other

Measure	Time frame	Description
Number of Participants With Markedly Abnormal Electrocardiographs	From the date of Screening until the date of last dose of study drug plus 30 days (Approximately 10 months)	—
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	From the date of first dose of study drug up to 30 days after the last dose of the study drug, up to approximately 10 months	Safety assessments consisted of monitoring and recording all AEs and SAEs, regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs and electrocardiograms; physical examinations; and Doppler sonography. AE severity was graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, where Grade 1 = mild, Grade 2 = moderate, Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death related to the AE. All AEs graded as 4 or 5 were considered to be serious. A treatment-emergent adverse event (TEAE) was defined as an AE that started on or after the date of first dose of study drug, up to 30 days after the last dose of study drug. For each category, a participant with two or more adverse events in that category was counted only once. Treatment-related TEAEs were considered by the investigator to be possibly or probably related to study drug or TEAEs with a missing causality.
Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Value (TEMAV) for Haematology	From the date of Screening until the date of last dose of study drug plus 30 days (Approximately 10 months)	—
Number of Participants With Clinically Significant Findings in Laboratory Values for Serum	From the date of Screening until the date of last dose of study drug plus 30 days (Approximately 10 months)	—
Number of Participants With Clinically Significant Findings in Laboratory Values for Urinalysis	From the date of Screening until the date of last dose of study drug plus 30 days (Approximately 10 months)	—
Number of Participants With Clinically Significant Change From Baseline in Vital Sign Values	From the date of Screening until the date of last dose of study drug plus 30 days (Approximately 10 months)	—

Countries

Japan

Participant flow

Pre-assignment details

A total of 56 participants were screened to enter into the study. Of these, 17 participants were screening failures, and 39 were randomized into the study. Of the 17 screening failures, 14 participants failed to meet the inclusion/exclusion criteria, 1 participant withdrew consent, and 2 participants were excluded for scheduling conflicts.

Participants by arm

Arm	Count
Placebo (60 mg) Participants took 60 mg placebo (3 x 20 mg matching placebo tablets) orally after a meal, once daily for 5 days.	11
Avatrombopag (20 mg) Participants took 20 mg avatrombopag (1 x 20 mg avatrombopag tablet and 2 x 20 mg matching placebo tablets) orally after a meal, once daily for 5 days.	7
Avatrombopag (40 mg) Avatrombopag (40 mg), Participants took 40 mg avatrombopag (2 x 20 mg avatrombopag tablets and 1 x 20 mg matching placebo tablet) orally after a meal, once daily for 5 days.	11
Avatrombopag (60 mg) Participants took 60 mg avatrombopag (3 x 20 mg avatrombopag tablets) orally, after a meal, once daily for 5 days.	10
Total	39

Baseline characteristics

Characteristic	Placebo (60 mg)	Avatrombopag (20 mg)	Avatrombopag (40 mg)	Avatrombopag (60 mg)	Total
Age, Continuous	71.1 years STANDARD_DEVIATION 8.49	64.6 years STANDARD_DEVIATION 8.42	64.6 years STANDARD_DEVIATION 9.59	62.1 years STANDARD_DEVIATION 7.32	65.8 years STANDARD_DEVIATION 8.92
Sex: Female, Male Female	4 Participants	1 Participants	5 Participants	3 Participants	13 Participants
Sex: Female, Male Male	7 Participants	6 Participants	6 Participants	7 Participants	26 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 11	0 / 7	0 / 11	0 / 10
other Total, other adverse events	8 / 11	4 / 7	8 / 11	3 / 10
serious Total, serious adverse events	0 / 11	0 / 7	0 / 11	0 / 10

Outcome results

Primary

Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L and at Least 20 x 10^9/L Increase From Baseline at Visit 4

Responders were defined as participants whose platelet count was greater than or equal to 50×10\^9/liter (L) and change from baseline was at least 20×10\^9/L at Visit 4. Participants receiving a platelet transfusion prior to the platelet count assessment at Visit 4 were considered as non-responders in the analysis. Two-sided 95% confidence interval (CI) is calculated by Clopper and Pearson method.

Time frame: Baseline and Visit 4 (Day 10)

Population: Full Analysis Set (FAS) included all randomized participants who received at least one dose of study drug.

Arm	Measure	Value (NUMBER)
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L and at Least 20 x 10^9/L Increase From Baseline at Visit 4	9.1 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L and at Least 20 x 10^9/L Increase From Baseline at Visit 4	28.6 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L and at Least 20 x 10^9/L Increase From Baseline at Visit 4	63.6 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L and at Least 20 x 10^9/L Increase From Baseline at Visit 4	40.0 Percentage of participants

p-value: 0.14695% CI: [-18.1, 57]Shirley-Williams test

p-value: 0.00495% CI: [21.4, 87.7]Shirley-Williams test

p-value: 0.02495% CI: [-3.9, 65.7]Shirley-Williams test

Secondary

Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit

Responders were defined as the participants whose platelet count greater than or equal to 150 x 10\^9/L by visit. Participants receiving a platelet transfusion prior to the platelet count assessment at Visit 4 were considered as non-responders in the analysis.

Time frame: Visit 3 (Day 4 or 5), Visit 4 (Day 10), Visit 5 (Day 17) and Visit 6 (Day 35)

Population: FAS

Arm	Measure	Group	Value (NUMBER)
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 3 (Day 4 or Day 5)	0.0 Percentage of participants
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 4 (Day 10)	0.0 Percentage of participants
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 5 (Day 17)	0.0 Percentage of participants
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 6 (Day 35)	0.0 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 4 (Day 10)	0.0 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 5 (Day 17)	0.0 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 6 (Day 35)	0.0 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 3 (Day 4 or Day 5)	0.0 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 5 (Day 17)	0.0 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 4 (Day 10)	0.0 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 6 (Day 35)	0.0 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 3 (Day 4 or Day 5)	0.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 6 (Day 35)	0.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 4 (Day 10)	0.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 3 (Day 4 or Day 5)	0.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 150 x 10^9/L At Each Visit	Visit 5 (Day 17)	0.0 Percentage of participants

Secondary

Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit

Responders were defined as the participants whose platelet count greater than or equal to 200 x 10\^9/L by visit. Participants receiving a platelet transfusion prior to the platelet count assessment at Visit 4 were considered as non-responders in the analysis.

Time frame: Visit 3 (Day 4 or 5), Visit 4 (Day 10), Visit 5 (Day 17) and Visit 6 (Day 35)

Population: FAS

Arm	Measure	Group	Value (NUMBER)
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 3 (Day 4 or Day 5)	0.0 Percentage of participants
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 4 (Day 10)	0.0 Percentage of participants
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 5 (Day 17)	0.0 Percentage of participants
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 6 (Day 35)	0.0 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 4 (Day 10)	0.0 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 5 (Day 17)	0.0 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 6 (Day 35)	0.0 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 3 (Day 4 or Day 5)	0.0 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 5 (Day 17)	0.0 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 4 (Day 10)	0.0 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 6 (Day 35)	0.0 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 3 (Day 4 or Day 5)	0.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 6 (Day 35)	0.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 4 (Day 10)	0.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 3 (Day 4 or Day 5)	0.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 200 x 10^9/L At Each Visit	Visit 5 (Day 17)	0.0 Percentage of participants

Secondary

Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit

Responders were defined as the participants whose platelet count greater than or equal to 50 x 10\^9/L by visit. Participants receiving a platelet transfusion prior to the platelet count assessment at Visit 4 were considered as non-responders in the analysis. Two-sided 95% CI is calculated by Clopper and Pearson method.

Time frame: Visit 3 (Day 4 or 5), Visit 4 (Day 10), Visit 5 (Day 17) and Visit 6 (Day 35)

Population: FAS

Arm	Measure	Group	Value (NUMBER)
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 3 (Day 4 or Day 5)	0.0 Percentage of participants
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 4 (Day 10)	9.1 Percentage of participants
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 5 (Day 17)	27.3 Percentage of participants
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 6 (Day 35)	18.2 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 4 (Day 10)	71.4 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 5 (Day 17)	0.0 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 6 (Day 35)	0.0 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 3 (Day 4 or Day 5)	14.3 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 5 (Day 17)	54.5 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 4 (Day 10)	81.8 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 6 (Day 35)	9.1 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 3 (Day 4 or Day 5)	27.3 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 6 (Day 35)	0.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 4 (Day 10)	50.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 3 (Day 4 or Day 5)	0.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 50 x 10^9/L at Each Visit	Visit 5 (Day 17)	20.0 Percentage of participants

Comparison: Visit 3 (Day 4 or Day 5)p-value: 0.38895% CI: [-11.6, 40.2]Fisher Exact

Comparison: Visit 3 (Day 4 or Day 5)p-value: 0.21495% CI: [1, 53.6]Fisher Exact

Comparison: Visit 4 (Day 10)p-value: 0.01295% CI: [24.8, 99.9]Fisher Exact

Comparison: Visit 4 (Day 10)p-value: 0.00195% CI: [44.3, 100]Fisher Exact

Comparison: Visit 4 (Day 10)p-value: 0.06395% CI: [5.6, 76.2]Fisher Exact

Comparison: Visit 5 (Day 17)p-value: 0.24595% CI: [-53.6, -1]Fisher Exact

Comparison: Visit 5 (Day 17)p-value: 0.38695% CI: [-12.2, 66.8]Fisher Exact

Comparison: Visit 5 (Day 17)p-value: 195% CI: [-43.4, 28.9]Fisher Exact

Comparison: Visit 6 (Day 35)p-value: 0.49695% CI: [-41, 4.6]Fisher Exact

Comparison: Visit 6 (Day 35)p-value: 195% CI: [-37.5, 19.3]Fisher Exact

Comparison: Visit 6 (Day 35)p-value: 0.47695% CI: [-41, 4.6]Fisher Exact

Secondary

Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit

Responders were defined as the participants whose platelet count greater than or equal to 75 x 10\^9/L by visit. Participants receiving a platelet transfusion prior to the platelet count assessment at Visit 4 were considered as non-responders in the analysis. Two-sided 95% CI is calculated by Clopper and Pearson method.

Time frame: Visit 3 (Day 4 or 5), Visit 4 (Day 10), Visit 5 (Day 17) and Visit 6 (Day 35)

Population: FAS

Arm	Measure	Group	Value (NUMBER)
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 3 (Day 4 or Day 5)	0.0 Percentage of participants
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 4 (Day 10)	0.0 Percentage of participants
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 5 (Day 17)	0.0 Percentage of participants
Placebo (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 6 (Day 35)	0.0 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 4 (Day 10)	0.0 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 5 (Day 17)	0.0 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 6 (Day 35)	0.0 Percentage of participants
Avatrombopag (20 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 3 (Day 4 or Day 5)	0.0 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 5 (Day 17)	0.0 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 4 (Day 10)	63.6 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 6 (Day 35)	0.0 Percentage of participants
Avatrombopag (40 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 3 (Day 4 or Day 5)	0.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 6 (Day 35)	0.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 4 (Day 10)	30.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 3 (Day 4 or Day 5)	0.0 Percentage of participants
Avatrombopag (60 mg)	Percentage of Participants With Platelet Count Greater Than or Equal to 75 x 10^9/L at Each Visit	Visit 5 (Day 17)	10.0 Percentage of participants

Comparison: Visit 4 (Day 10)p-value: 0.00395% CI: [35.2, 92.1]Fisher Exact

Comparison: Visit 4 (Day 10)p-value: 0.0995% CI: [1.6, 58.4]Fisher Exact

Comparison: Visit 5 (Day 17)p-value: 0.47695% CI: [-8.6, 28.6]Fisher Exact

Secondary

Platelet Count and Change From Baseline in Platelet Count by Visit

Time frame: Baseline, Visit 3 (Day 4 or 5), Visit 4 (Day 10), Visit 5 (Day 17) and Visit 6 (Day 35)

Population: FAS

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 5 (Day 17) Platelet count	40.10 Number of platelets x 10^9/L	Standard Deviation 9.916
Placebo (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 6 (Day 35) Platelet count	41.50 Number of platelets x 10^9/L	Standard Deviation 10.845
Placebo (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 4 (Day 10) Change from baseline	3.32 Number of platelets x 10^9/L	Standard Deviation 7.163
Placebo (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 3 (Day 4 or Day 5) Change from baseline	0.68 Number of platelets x 10^9/L	Standard Deviation 2.848
Placebo (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 6 (Day 35) Change from baseline	1.80 Number of platelets x 10^9/L	Standard Deviation 4.614
Placebo (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 3 (Day 4 or Day 5) Platelet count	41.27 Number of platelets x 10^9/L	Standard Deviation 8.344
Placebo (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 5 (Day 17) Change from baseline	0.40 Number of platelets x 10^9/L	Standard Deviation 5.243
Placebo (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 4 (Day 10) Platelet count	43.91 Number of platelets x 10^9/L	Standard Deviation 10.568
Placebo (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 2 (Baseline) Platelet count	40.59 Number of platelets x 10^9/L	Standard Deviation 7.024
Avatrombopag (20 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 4 (Day 10) Platelet count	53.29 Number of platelets x 10^9/L	Standard Deviation 5.678
Avatrombopag (20 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 5 (Day 17) Platelet count	41.33 Number of platelets x 10^9/L	Standard Deviation 4.803
Avatrombopag (20 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 4 (Day 10) Change from baseline	12.71 Number of platelets x 10^9/L	Standard Deviation 9.486
Avatrombopag (20 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 2 (Baseline) Platelet count	40.57 Number of platelets x 10^9/L	Standard Deviation 5.556
Avatrombopag (20 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 6 (Day 35) Change from baseline	0.08 Number of platelets x 10^9/L	Standard Deviation 1.686
Avatrombopag (20 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 3 (Day 4 or Day 5) Platelet count	44.71 Number of platelets x 10^9/L	Standard Deviation 6.102
Avatrombopag (20 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 5 (Day 17) Change from baseline	1.75 Number of platelets x 10^9/L	Standard Deviation 3.402
Avatrombopag (20 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 3 (Day 4 or Day 5) Change from baseline	4.14 Number of platelets x 10^9/L	Standard Deviation 7.099
Avatrombopag (20 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 6 (Day 35) Platelet count	39.67 Number of platelets x 10^9/L	Standard Deviation 5.574
Avatrombopag (40 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 5 (Day 17) Change from baseline	14.50 Number of platelets x 10^9/L	Standard Deviation 11.874
Avatrombopag (40 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 2 (Baseline) Platelet count	41.23 Number of platelets x 10^9/L	Standard Deviation 5.159
Avatrombopag (40 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 3 (Day 4 or Day 5) Platelet count	46.09 Number of platelets x 10^9/L	Standard Deviation 8.86
Avatrombopag (40 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 3 (Day 4 or Day 5) Change from baseline	4.86 Number of platelets x 10^9/L	Standard Deviation 6.569
Avatrombopag (40 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 4 (Day 10) Platelet count	79.36 Number of platelets x 10^9/L	Standard Deviation 24.8
Avatrombopag (40 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 4 (Day 10) Change from baseline	38.14 Number of platelets x 10^9/L	Standard Deviation 22.781
Avatrombopag (40 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 5 (Day 17) Platelet count	55.73 Number of platelets x 10^9/L	Standard Deviation 14.826
Avatrombopag (40 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 6 (Day 35) Platelet count	41.36 Number of platelets x 10^9/L	Standard Deviation 8.262
Avatrombopag (40 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 6 (Day 35) Change from baseline	0.14 Number of platelets x 10^9/L	Standard Deviation 8.382
Avatrombopag (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 5 (Day 17) Platelet count	41.80 Number of platelets x 10^9/L	Standard Deviation 16.578
Avatrombopag (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 3 (Day 4 or Day 5) Change from baseline	3.85 Number of platelets x 10^9/L	Standard Deviation 6.223
Avatrombopag (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 3 (Day 4 or Day 5) Platelet count	32.70 Number of platelets x 10^9/L	Standard Deviation 9.967
Avatrombopag (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 6 (Day 35) Change from baseline	2.33 Number of platelets x 10^9/L	Standard Deviation 4.265
Avatrombopag (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 6 (Day 35) Platelet count	31.44 Number of platelets x 10^9/L	Standard Deviation 8.353
Avatrombopag (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 2 (Baseline) Platelet count	28.85 Number of platelets x 10^9/L	Standard Deviation 7.568
Avatrombopag (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 4 (Day 10) Change from baseline	27.05 Number of platelets x 10^9/L	Standard Deviation 22.7
Avatrombopag (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 4 (Day 10) Platelet count	55.90 Number of platelets x 10^9/L	Standard Deviation 22.507
Avatrombopag (60 mg)	Platelet Count and Change From Baseline in Platelet Count by Visit	Visit 5 (Day 17) Change from baseline	12.95 Number of platelets x 10^9/L	Standard Deviation 12.857

Comparison: Visit 3 (Day 4 or Day 5)p-value: 0.296Wilcoxon (Mann-Whitney)

Comparison: Visit 3 (Day 4 or Day 5)p-value: 0.07Wilcoxon (Mann-Whitney)

Comparison: Visit 3 (Day 4 or Day 5)p-value: 0.138Wilcoxon (Mann-Whitney)

Comparison: Visit 4 (Day 10)p-value: 0.012Wilcoxon (Mann-Whitney)

Comparison: Visit 4 (Day 10)p-value: 0.001Wilcoxon (Mann-Whitney)

Comparison: Visit 5 (Day 17)p-value: 0.624Wilcoxon (Mann-Whitney)

Comparison: Visit 5 (Day 17)p-value: 0.009Wilcoxon (Mann-Whitney)

Comparison: Visit 5 (Day 17)p-value: 0.01Wilcoxon (Mann-Whitney)

Comparison: Visit 6 (Day 35)p-value: 0.154Wilcoxon (Mann-Whitney)

Comparison: Visit 6 (Day 35)p-value: 0.216Wilcoxon (Mann-Whitney)

Comparison: Visit 6 (Day 35)p-value: 0.901Wilcoxon (Mann-Whitney)

Other Pre-specified

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Safety assessments consisted of monitoring and recording all AEs and SAEs, regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs and electrocardiograms; physical examinations; and Doppler sonography. AE severity was graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, where Grade 1 = mild, Grade 2 = moderate, Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death related to the AE. All AEs graded as 4 or 5 were considered to be serious. A treatment-emergent adverse event (TEAE) was defined as an AE that started on or after the date of first dose of study drug, up to 30 days after the last dose of study drug. For each category, a participant with two or more adverse events in that category was counted only once. Treatment-related TEAEs were considered by the investigator to be possibly or probably related to study drug or TEAEs with a missing causality.

Time frame: From the date of first dose of study drug up to 30 days after the last dose of the study drug, up to approximately 10 months

Population: Safety Analysis Set included all participants who received at least one dose of study drug and had at least one safety assessment.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Placebo (60 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	All TEAEs	8 Participants
Placebo (60 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug dose reduction	0 Participants
Placebo (60 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug withdrawal	0 Participants
Placebo (60 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Treatment-related TEAEs	0 Participants
Placebo (60 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug dose interruption	0 Participants
Placebo (60 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Serious TEAEs	0 Participants
Placebo (60 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug dose adjustment	0 Participants
Avatrombopag (20 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug dose reduction	0 Participants
Avatrombopag (20 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug dose adjustment	0 Participants
Avatrombopag (20 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Serious TEAEs	0 Participants
Avatrombopag (20 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug withdrawal	0 Participants
Avatrombopag (20 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug dose interruption	0 Participants
Avatrombopag (20 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Treatment-related TEAEs	2 Participants
Avatrombopag (20 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	All TEAEs	4 Participants
Avatrombopag (40 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug dose adjustment	0 Participants
Avatrombopag (40 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	All TEAEs	8 Participants
Avatrombopag (40 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Treatment-related TEAEs	2 Participants
Avatrombopag (40 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Serious TEAEs	0 Participants
Avatrombopag (40 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug withdrawal	0 Participants
Avatrombopag (40 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug dose reduction	0 Participants
Avatrombopag (40 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug dose interruption	0 Participants
Avatrombopag (60 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Serious TEAEs	0 Participants
Avatrombopag (60 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug dose interruption	0 Participants
Avatrombopag (60 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug dose reduction	0 Participants
Avatrombopag (60 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Treatment-related TEAEs	0 Participants
Avatrombopag (60 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	All TEAEs	3 Participants
Avatrombopag (60 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug withdrawal	0 Participants
Avatrombopag (60 mg)	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	TEAEs leading to study drug dose adjustment	0 Participants

Other Pre-specified

Number of Participants With Clinically Significant Change From Baseline in Vital Sign Values

Time frame: From the date of Screening until the date of last dose of study drug plus 30 days (Approximately 10 months)