Treatment of Thrombocytopenia in Patients With Chronic Liver DiseaseUndergoing an Elective Procedure

• Sponsor: Eisai Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01972529
• Collaborator: (none)
• Enrollment: 231
• Locations: 110
• Arms: 4
• Actual Duration (Months): 36.9
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a global, multicenter, randomized, double-blind, placebo-controlled, parallel group study using avatrombopag to treat adults with thrombocytopenia associated with liver disease. The study will evaluate avatrombopag in the treatment of thrombocytopenia associated with liver disease prior to an elective procedure to reduce the need for platelet transfusions or any rescue procedure for bleeding due to procedural and post-procedural bleeding complications. Participants will be enrolled into 2 cohorts according to mean baseline platelet count and, within each baseline platelet count cohort will be further stratified by risk of bleeding associated with the elective procedure (low, moderate, or high) and hepatocellular carcinoma (HCC) status (Yes or No).

Condition or Disease	Intervention/Treatment	Phase
Thrombocytopenia Associated With Liver Disease	Drug: avatrombopag (lower baseline platelet count); Drug: placebo (lower baseline platelet count); Drug: avatrombopag (higher baseline platelet count); Drug: placebo (higher baseline platelet count)	Phase 3

Detailed Description

This study will consist of 3 phases: Prerandomization, Randomization, and a Follow-up Phase. The Prerandomization Phase includes one Screening Visit that will take place from Day -14 through Day -1; the Randomization Phase includes the Baseline Period, Treatment Period, and Procedure Day Period (5 to 8 days after last dose of study drug [Study Day 10 to 13]). The Follow-up Phase comprises 2 visits: 7 days post Procedure Day and 30 days after receiving the last dose of study drug. Permitted procedures include: Paracentesis; Thoracentesis; Gastrointestinal endoscopy with or without plans for biopsy, colonoscopy, polypectomy, or variceal banding; Liver biopsy; Bronchoscopy with or without plans for biopsy; Ethanol ablation therapy or chemoembolization for HCC; Vascular catheterization (including right side procedures in participants with pulmonary hypertension); Transjugular intrahepatic portosystemic shunt; Dental procedures; Renal biopsy; Biliary interventions; Nephrostomy tube placement; Radiofrequency ablation; and Laparoscopic interventions.

Study Design

• Study Type: Interventional
• Actual Enrollment: 231 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Global, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of Once-daily Oral Avatrombopag for the Treatment of Adults With Thrombocytopenia Associated With Liver Disease Prior to an Elective Procedure
• Actual Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: Jan 26, 2017
• Actual Study Completion Date: Feb 27, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A (avatrombopag, lower baseline platelet count) 60 mg avatrombopag (3 x 20 mg tablets) once daily on Days 1 through 5	Drug: avatrombopag (lower baseline platelet count); 60 mg avatrombopag (3 x 20 mg tablets)
Placebo Comparator: Group B (placebo, lower baseline platelet count) placebo (3 x 20 mg matching placebo tablets) once daily on Days 1 through 5	Drug: placebo (lower baseline platelet count); 60 mg placebo (3 x 20 mg matching placebo tablets)
Experimental: Group C (avatrombopag, higher baseline platelet count) 40 mg avatrombopag (2 x 20 mg tablets) once daily on Days 1 through 5	Drug: avatrombopag (higher baseline platelet count); 40 mg avatrombopag (2 x 20 mg tablets)
Placebo Comparator: Group D (placebo, higher baseline platelet count) placebo (2 x 20 mg matching placebo tablets) once daily on Days 1 through 5	Drug: placebo (higher baseline platelet count); 40 mg placebo (2 x 20 mg matching placebo tablets)

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Did Not Require a Platelet Transfusion or Any Rescue Procedure for Bleeding After Randomization Following a Scheduled Procedure [Baseline (Visit 2) up to 7 days following a scheduled procedure]

   Responders were defined as participants who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure. Participants with missing information due to early withdrawal or other reasons were conservatively considered as having received a transfusion in the analysis, (i.e. a Non-responder).

Secondary Outcome Measures

1. Percentage of Participants Who Achieved a Platelet Count Greater Than or Equal to 50 x 10^9/L on the Scheduled Procedure Day [Day 10 to Day 13 (Visit 4)]

   Responders were defined as participants who achieved a platelet count greater than or equal to 50 x 10^9/L on the procedure day. Participants with missing a platelet count on the procedure day were conservatively considered as not achieving a platelet count of 50x10^9/L in the analysis, (i.e. Non-responders).

2. Change From Baseline in Platelet Count on the Scheduled Procedure Day [Baseline (Visit 2) to Procedure Day 10 to Day 13 (Visit 4)]

   Last observation carried forward was used for participants with a missing platelet count on the scheduled procedure day. Platelet count was measured preprocedure and before any platelet transfusion.

Other Outcome Measures

1. Percentage of Participants With a World Health Organization (WHO) Bleeding Score Greater Than or Equal to 2 After a Scheduled Procedure [Baseline (Visit 2) up to 7 days post scheduled procedure]

   The severity of bleeding events was assessed by the investigator (or appropriately delegated study site personnel) using the WHO bleeding scale. The WHO bleeding scale is a clinical investigator-assessed five-point scale with Grade 0 = No bleeding, Grade 1 = Petechial bleeding, Grade 2 = Mild blood loss (clinically significant), Grade 3 = Gross blood loss (requires transfusion (severe)), and Grade 4 = Debilitating blood loss, retinal or cerebral associated with fatality. Participants with missing information are considered as having a WHO bleeding score greater than or equal to 2 in the analysis.

2. Number of Participants Experiencing an Adverse Event [From date of first dose of study drug up to 30 days after the last dose of study drug, up to approximately 3 years]

   Safety assessments consisted of monitoring and recording all adverse events (AEs) and serious adverse events, including platelet transfusion-related complications; routine laboratory evaluation for hematology, serum chemistry, and urine values; periodic measurement of vital signs and electrocardiograms (ECGs); the performance of 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. Treatment-emergent adverse events (TEAEs) were 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. Treatment-related AEs were considered by the investigator to be possibly or probably related to study drug.

Eligibility Criteria

Criteria

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

Inclusion Criteria

1. Participants greater than or equal to 18 years of age at Screening with chronic liver disease

2. Participants who have a mean baseline platelet count of less than 50 x 10^{9/L. Platelet counts must 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. The mean of these 2 platelet counts (mean baseline platelet count) will be used for entry criteria and for assignment to the low or high baseline platelet count cohort.

3. Participants scheduled to undergo a permitted elective procedure who, in the opinion of the investigator, will require a platelet transfusion to address a risk of bleeding associated with the procedure unless there is a clinically significant increase in platelet count from baseline

4. Model For End-stage Liver Disease (MELD) score less than or equal to 24 at Screening

5. If taking inhibitors of P glycoprotein (P-gp), except for verapamil, dose must be stable for 7 days prior to Screening

6. Provide written informed consent

7. 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 <10 centimeters/second at Screening

4. Hepatic encephalopathy that cannot be effectively treated

5. Participants 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. Elective procedure performed prior to Visit 4 (Procedure Day)

14. Known to be human immunodeficiency virus positive

15. Any clinically significant acute or active bleeding (eg, gastrointestinal, central nervous system)

16. Known history of any primary hematologic disorder (eg, immune thrombocytopenic purpura, myelodysplastic syndrome)

17. Known medical history of genetic prothrombotic syndromes (eg, Factor V Leiden; prothrombin G20210A; ATIII deficiency, etc.)

18. Participants 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)

19. 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 participant 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.

20. 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.

21. Post liver transplant participants

22. Any participant who has previously received avatrombopag

23. Hypersensitivity to avatrombopag maleate or any of its excipients

24. Hemoglobin levels ≤ 8.0 or ≥ 18.0 g/dL for men and > 15 for women at Screening, with hematocrit ≥ 54% for men and ≥ 45% for women

25. Current malignancy including solid tumors and hematologic malignancies (except HCC)

26. Any history of concomitant medical condition that, in the opinion of the investigator(s), would compromise the participant's ability to safely complete the study

27. Currently enrolled in another clinical trial with any investigational drug or device within 30 days of Screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Lancaster	California	United States
2		Long Beach	California	United States
3		Los Angeles	California	United States
4		Sacramento	California	United States
5		San Bernardino	California	United States
6		San Francisco	California	United States
7		Jacksonville	Florida	United States
8		Palmetto Bay	Florida	United States
9		Tampa	Florida	United States
10		New Orleans	Louisiana	United States
11		Rochester	Michigan	United States
12		Minneapolis	Minnesota	United States
13		Jackson	Mississippi	United States
14		Bronx	New York	United States
15		New York	New York	United States
16		Philadelphia	Pennsylvania	United States
17		Pittsburgh	Pennsylvania	United States
18		Dallas	Texas	United States
19		Harlingen	Texas	United States
20		Houston	Texas	United States
21		San Antonio	Texas	United States
22		Pilar	Buenos Aires	Argentina
23		Ciudad Autonoma Buenos Aires		Argentina
24		Mendoza		Argentina
25		Camperdown	New South Wales	Australia
26		Adelaide	South Australia	Australia
27		Bedford Park	South Australia	Australia
28		Linz		Austria
29		Vienna		Austria
30		Wien		Austria
31		Bruxelles		Belgium
32		Leuven		Belgium
33		Porto Alegre	Rio Grande Do Sul	Brazil
34		Sao Jose do Rio Preto	Sao Paulo	Brazil
35		Sao Paulo		Brazil
36		London	Ontario	Canada
37		Toronto	Ontario	Canada
38		La Serena		Chile
39		Santiago		Chile
40		Changsha	Hunan	China
41		Nanjing	Jiangsu	China
42		Shanghai	Shanghai	China
43		Beijing		China
44		Strasbourg	Bas Rhin	France
45		Grenoble cedex 9	Isere	France
46		Reims	Marne	France
47		Clermont Ferrand cedex 1	Puy De Dome	France
48		Amiens cedex 1	Somme	France
49		Vandoeuvre les Nancy		France
50		Freiburg	Baden Wuerttemberg	Germany
51		Herne	Nordrhein Westfalen	Germany
52		Koeln	Nordrhein Westfalen	Germany
53		Kiel	Schleswig Holstein	Germany
54		Hamburg		Germany
55		Bekescsaba		Hungary
56		Budapest		Hungary
57		Dunaujvaros		Hungary
58		Gyula		Hungary
59		Kaposvar		Hungary
60		Kecskemet		Hungary
61		Szombathely		Hungary
62		Zalaegerszeg		Hungary
63		San Giovanni Rotondo	Foggia	Italy
64		Bari		Italy
65		Bologna		Italy
66		Genova		Italy
67		Milano		Italy
68		Modena		Italy
69		Palermo		Italy
70		Udine		Italy
71		Chuncheon	Gangwon-do	Korea, Republic of
72		Guri-si	Gyeonggi-do	Korea, Republic of
73		Seongnam-Si	Gyeonggi-do	Korea, Republic of
74		Suwon	Gyeonggi-do	Korea, Republic of
75		Yangsan	Gyeongnam	Korea, Republic of
76		Hwasun	Jeollanam-do	Korea, Republic of
77		Busan		Korea, Republic of
78		Daegu		Korea, Republic of
79		Incheon		Korea, Republic of
80		Seoul		Korea, Republic of
81		Katowice		Poland
82		Lodz		Poland
83		Myslowice		Poland
84		Szczecin		Poland
85		Wroclaw		Poland
86		Coimbra		Portugal
87		Lisboa		Portugal
88		Porto		Portugal
89		Viana do Castelo		Portugal
90		Vila Real		Portugal
91		Viseu		Portugal
92		Barcelona		Spain
93		Pontevedra		Spain
94		Sevilla		Spain
95		Valencia		Spain
96		Valladolid		Spain
97		Kaohsiung		Taiwan
98		Taichung		Taiwan
99		Tainan		Taiwan
100		Taipei		Taiwan
101		Taoyuan City		Taiwan
102		Bangkoknoi	Bangkok	Thailand
103		Ratchathewi	Bangkok	Thailand
104		Mueang Nonthaburi	Chiang Mai	Thailand
105		Khlong Luang	Pathumthani	Thailand
106		Truro	Cornwall	United Kingdom
107		London	Greater London	United Kingdom
108		Manchester	Greater Manchester	United Kingdom
109		Wolverhampton	West Midlands	United Kingdom
110		Leeds	West Yorkshire	United Kingdom

Sponsors and Collaborators

• Eisai Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Dec 2, 2016
• Statistical Analysis Plan - Feb 16, 2017

More Information

Publications

None provided.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT01972529
• Other Study ID Numbers: E5501-G000-310; 2013-000965-34
• First Posted: Oct 30, 2013
• Last Update Posted: Feb 27, 2018
• Last Verified: Jan 1, 2018

• Keywords provided by Eisai Inc.: Thrombocytopenia; Chronic Liver Disease
• Additional relevant MeSH terms: Liver Diseases; Thrombocytopenia

Study Results

Participant Flow

Pre-assignment Detail	A total of 370 participants signed informed consent. Of these 370 participants, 139 were screening failures and 231 were randomized into the study. Of the 139 screening failures, 120 did not meet the inclusion/exclusion criteria and the other 19 participants failed due to adverse events, lost to follow-up and withdrawal of consent.

Arm/Group Title	60 mg Placebo (Lower Baseline Platelet Count)	60 mg Avatrombopag, (Lower Baseline Platelet Count)	40 mg Placebo (Higher Baseline Platelet Count)	40 mg Avatrombopag (Higher Baseline Platelet Count)
Arm/Group Description	Participants with a baseline platelet count of less than 40 x 10^9/liters (L) took three 20 milligrams (mg) (60 mg total) matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of less than 40 x 10^9/L took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the elective procedure.	Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg tablets (40 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.
Period Title: Overall Study
STARTED	48	90	34	59
COMPLETED	46	85	32	55
NOT COMPLETED	2	5	2	4

Baseline Characteristics

Arm/Group Title	60 mg Placebo (Lower Baseline Platelet Count)	60 mg Avatrombopag, (Lower Baseline Platelet Count)	40 mg Placebo (Higher Baseline Platelet Count)	40 mg Avatrombopag (Higher Baseline Platelet Count)	Total
Arm/Group Description	Participants with a baseline platelet count of less than 40 x 10^9/liters (L) took three 20 milligrams (mg) matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of less than 40 x 10^9/L took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg tablets (40 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Total of all reporting groups
Overall Participants	48	90	34	59	231
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55.1 (11.02)	55.6 (9.12)	57.8 (11.05)	57.5 (10.06)	56.3 (10.06)
Sex: Female, Male (Count of Participants)
Female	16 33.3%	25 27.8%	10 29.4%	22 37.3%	73 31.6%
Male	32 66.7%	65 72.2%	24 70.6%	37 62.7%	158 68.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 20.8%	10 11.1%	3 8.8%	7 11.9%	30 13%
Not Hispanic or Latino	37 77.1%	77 85.6%	31 91.2%	51 86.4%	196 84.8%
Unknown or Not Reported	1 2.1%	3 3.3%	0 0%	1 1.7%	5 2.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	18 37.5%	32 35.6%	15 44.1%	24 40.7%	89 38.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	3 3.3%	0 0%	2 3.4%	5 2.2%
White	28 58.3%	50 55.6%	19 55.9%	31 52.5%	128 55.4%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	2 4.2%	5 5.6%	0 0%	2 3.4%	9 3.9%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Did Not Require a Platelet Transfusion or Any Rescue Procedure for Bleeding After Randomization Following a Scheduled Procedure
Description	Responders were defined as participants who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure. Participants with missing information due to early withdrawal or other reasons were conservatively considered as having received a transfusion in the analysis, (i.e. a Non-responder).
Time Frame	Baseline (Visit 2) up to 7 days following a scheduled procedure

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS) was defined as the group of all randomized participants.

Arm/Group Title	60 mg Placebo (Lower Baseline Platelet Count)	60 mg Avatrombopag, (Lower Baseline Platelet Count)	40 mg Placebo (Higher Baseline Platelet Count)	40 mg Avatrombopag (Higher Baseline Platelet Count)
Arm/Group Description	Participants with a baseline platelet count of less than 40 x 10^9/liters (L ) took three 20 milligrams (mg) matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of less than 40 x 10^9/L took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg tablets (40 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.
Measure Participants	48	90	34	59
Number (95% Confidence Interval) [Percentage of participants]	22.9 47.7%	65.6 72.9%	38.2 112.4%	88.1 149.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	60 mg Placebo (Lower Baseline Platelet Count), 60 mg Avatrombopag, (Lower Baseline Platelet Count)
	Comments	The null hypothesis was that the proportion of participants not requiring a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure was the same between the 60 mg avatrombopag and matched placebo treatment groups.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by the risk of bleeding associated with the elective procedure within each baseline platelet count cohort.
Method of Estimation	Estimation Parameter	Difference of proportion vs placebo
	Estimated Value	42.6
	Confidence Interval	(2-Sided) 95%; 27.2 to 58.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of proportion versus (vs) placebo = proportion of Responders for avatrombopag - proportion of Responders for placebo; 95% CI is calculated based on normal approximation.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	40 mg Placebo (Higher Baseline Platelet Count), 40 mg Avatrombopag (Higher Baseline Platelet Count)
	Comments	The null hypothesis was that the proportion of participants not requiring a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure was the same between the avatrombopag and placebo treatment groups.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by the risk of bleeding associated with the elective procedure within each baseline platelet count cohort.
Method of Estimation	Estimation Parameter	Difference of proportion vs placebo
	Estimated Value	49.9
	Confidence Interval	(2-Sided) 95%; 31.6 to 68.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of proportion vs placebo = proportion of Responders for avatrombopag - proportion of Responders for placebo; 95% CI is calculated based on normal approximation.

2. Secondary Outcome

Title	Percentage of Participants Who Achieved a Platelet Count Greater Than or Equal to 50 x 10^9/L on the Scheduled Procedure Day
Description	Responders were defined as participants who achieved a platelet count greater than or equal to 50 x 10^9/L on the procedure day. Participants with missing a platelet count on the procedure day were conservatively considered as not achieving a platelet count of 50x10^9/L in the analysis, (i.e. Non-responders).
Time Frame	Day 10 to Day 13 (Visit 4)

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	60 mg Placebo (Lower Baseline Platelet Count)	60 mg Avatrombopag, (Lower Baseline Platelet Count)	40 mg Placebo (Higher Baseline Platelet Count)	40 mg Avatrombopag (Higher Baseline Platelet Count)
Arm/Group Description	Participants with a baseline platelet count of less than 40 x 10^9/L took three 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of less than 40 x 10^9/L took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg tablets (40 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.
Measure Participants	48	90	34	59
Number (95% Confidence Interval) [Percentage of participants]	4.2 8.8%	68.9 76.6%	20.6 60.6%	88.1 149.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	60 mg Placebo (Lower Baseline Platelet Count), 60 mg Avatrombopag, (Lower Baseline Platelet Count)
	Comments	The null hypothesis was that the proportion of participants not requiring a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure was the same between the avatrombopag and placebo treatment groups
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value is stratified by the risk of bleeding associated with the elective procedure within each baseline platelet count cohort.
Method of Estimation	Estimation Parameter	Difference of proportion vs placebo
	Estimated Value	64.7
	Confidence Interval	(2-Sided) 95%; 53.6 to 75.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of proportion vs placebo = proportion of responders for avatrombopag - proportion of responders for placebo; 95% CI is calculated based on normal approximation.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	40 mg Placebo (Higher Baseline Platelet Count), 40 mg Avatrombopag (Higher Baseline Platelet Count)
	Comments	The null hypothesis was that the proportion of participants not requiring a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure was the same between the avatrombopag and placebo treatment groups
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value is stratified by the risk of bleeding associated with the elective procedure within each baseline platelet count cohort.
Method of Estimation	Estimation Parameter	Difference of percentage vs placebo
	Estimated Value	67.5
	Confidence Interval	(2-Sided) 95%; 51.6 to 83.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of proportion vs placebo = proportion of responders for avatrombopag - proportion of responders for placebo; 95% CI is calculated based on normal approximation.

3. Secondary Outcome

Title	Change From Baseline in Platelet Count on the Scheduled Procedure Day
Description	Last observation carried forward was used for participants with a missing platelet count on the scheduled procedure day. Platelet count was measured preprocedure and before any platelet transfusion.
Time Frame	Baseline (Visit 2) to Procedure Day 10 to Day 13 (Visit 4)

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	60 mg Placebo (Lower Baseline Platelet Count)	60 mg Avatrombopag, (Lower Baseline Platelet Count)	40 mg Placebo (Higher Baseline Platelet Count)	40 mg Avatrombopag (Higher Baseline Platelet Count)
Arm/Group Description	Participants with a baseline platelet count of less than 40 x 10^9/L took three 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of less than 40 x 10^9/L took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg tablets (40 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.
Measure Participants	48	88	32	58
Mean (Standard Deviation) [Platelet count x 10^9/per liter]	0.8 (6.36)	32.0 (25.53)	1.0 (9.30)	37.1 (27.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	60 mg Placebo (Lower Baseline Platelet Count), 60 mg Avatrombopag, (Lower Baseline Platelet Count)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	P-value is based on Wilcoxon rank sum test for each avatrombopag treatment group vs placebo within each baseline platelet count cohort.
Method of Estimation	Estimation Parameter	Difference in change of platelet count
	Estimated Value	27.5
	Confidence Interval	(2-Sided) 95%; 22.5 to 32.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in change from baseline of platelet count for avatrombopag vs placebo within each baseline platelet count cohort is based on Hodges-Lehmann estimation; 95% confidence interval is the asymptotic (Moses) CI.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	40 mg Placebo (Higher Baseline Platelet Count), 40 mg Avatrombopag (Higher Baseline Platelet Count)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	P-value is based on Wilcoxon rank sum test for each avatrombopag treatment group vs placebo within each baseline platelet count cohort.
Method of Estimation	Estimation Parameter	Difference in change of platelet count
	Estimated Value	33.0
	Confidence Interval	(2-Sided) 95%; 25.5 to 41.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in change from baseline of platelet count for avatrombopag vs placebo within each baseline platelet count cohort is based on Hodges-Lehmann estimation; 95% confidence interval is the asymptotic (Moses) CI.

4. Other Pre-specified Outcome

Title	Percentage of Participants With a World Health Organization (WHO) Bleeding Score Greater Than or Equal to 2 After a Scheduled Procedure
Description	The severity of bleeding events was assessed by the investigator (or appropriately delegated study site personnel) using the WHO bleeding scale. The WHO bleeding scale is a clinical investigator-assessed five-point scale with Grade 0 = No bleeding, Grade 1 = Petechial bleeding, Grade 2 = Mild blood loss (clinically significant), Grade 3 = Gross blood loss (requires transfusion (severe)), and Grade 4 = Debilitating blood loss, retinal or cerebral associated with fatality. Participants with missing information are considered as having a WHO bleeding score greater than or equal to 2 in the analysis.
Time Frame	Baseline (Visit 2) up to 7 days post scheduled procedure

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	60 mg Placebo (Lower Baseline Platelet Count)	60 mg Avatrombopag, (Lower Baseline Platelet Count)	40 mg Placebo (Higher Baseline Platelet Count)	40 mg Avatrombopag (Higher Baseline Platelet Count)
Arm/Group Description	Participants with a baseline platelet count of less than 40 x 10^9/L took three 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of less than 40 x 10^9/L took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg tablets (40 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.
Measure Participants	48	90	34	59
Number [Percentage of participants]	6.3 13.1%	5.6 6.2%	2.9 8.5%	0 0%

5. Other Pre-specified Outcome

Title	Number of Participants Experiencing an Adverse Event
Description	Safety assessments consisted of monitoring and recording all adverse events (AEs) and serious adverse events, including platelet transfusion-related complications; routine laboratory evaluation for hematology, serum chemistry, and urine values; periodic measurement of vital signs and electrocardiograms (ECGs); the performance of 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. Treatment-emergent adverse events (TEAEs) were 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. Treatment-related AEs were considered by the investigator to be possibly or probably related to study drug.
Time Frame	From date of first dose of study drug up to 30 days after the last dose of study drug, up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of study drug and had at least 1 postdose safety assessment.

Arm/Group Title	60 mg Placebo (Lower Baseline Platelet Count)	60 mg Avatrombopag, (Lower Baseline Platelet Count)	40 mg Placebo (Higher Baseline Platelet Count)	40 mg Avatrombopag (Higher Baseline Platelet Count)
Arm/Group Description	Participants with a baseline platelet count of less than 40 x 10^9/L took three 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of less than 40 x 10^9/L took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.	Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg tablets (40 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.
Measure Participants	48	89	32	58
TEAEs	31 64.6%	53 58.9%	18 52.9%	31 52.5%
Treatment-related TEAEs	7 14.6%	12 13.3%	2 5.9%	4 6.8%
Serious TEAEs	11 22.9%	10 11.1%	1 2.9%	8 13.6%
TEAEs leading to study drug dose adjustment	0 0%	2 2.2%	0 0%	0 0%
TEAEs leading to study drug withdrawal	0 0%	2 2.2%	0 0%	0 0%
TEAEs leading to study drug dose reduction	0 0%	0 0%	0 0%	0 0%

Adverse Events

Time Frame	From date of administration of first dose up to 30 days after the last dose, up to approximately 3 years
Adverse Event Reporting Description	Treatment-emergent adverse events and all serious adverse events were reported. Adverse events were graded using Common Terminology Criteria for Adverse Event version 4. Safety analysis set included all participants who received at least 1 dose of study drug and had at least 1 post dose safety assessment. This set was analyzed "as treated".
Arm/Group Title	60 mg Placebo (Lower Baseline Platelet Count)		60 mg Avatrombopag, (Lower Baseline Platelet Count)		40 mg Placebo (Higher Baseline Platelet Count)		40 mg Avatrombopag (Higher Baseline Platelet Count)
Arm/Group Description	Participants with a baseline platelet count of less than 40 x 10^9/liters (L) took three 20 milligrams (mg) matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.		Participants with a baseline platelet count of less than 40 x 10^9/L took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.		Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.		Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg tablets (40 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.
All Cause Mortality
	60 mg Placebo (Lower Baseline Platelet Count)		60 mg Avatrombopag, (Lower Baseline Platelet Count)		40 mg Placebo (Higher Baseline Platelet Count)		40 mg Avatrombopag (Higher Baseline Platelet Count)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/48 (0%)		0/89 (0%)		0/32 (0%)		2/58 (3.4%)
Serious Adverse Events
	60 mg Placebo (Lower Baseline Platelet Count)		60 mg Avatrombopag, (Lower Baseline Platelet Count)		40 mg Placebo (Higher Baseline Platelet Count)		40 mg Avatrombopag (Higher Baseline Platelet Count)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/48 (22.9%)		10/89 (11.2%)		1/32 (3.1%)		8/58 (13.8%)
Blood and lymphatic system disorders
Anaemia	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Splenomeglay	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Stress polycythaemia	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Haemorrhagic anaemia	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Splenic haemorrhage	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Splenic infarction	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Ear and labyrinth disorders
Vertigo	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Gastrointestinal disorders
Abdominal pain	0/48 (0%)		0/89 (0%)		0/32 (0%)		1/58 (1.7%)
Abdominal Pain Upper	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Ascites	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Diarrhoea	0/48 (0%)		1/89 (1.1%)		1/32 (3.1%)		0/58 (0%)
Upper gastrointestinal haemorrhage	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		1/58 (1.7%)
Oesophageal varices haemorrhage	0/48 (0%)		0/89 (0%)		0/32 (0%)		1/58 (1.7%)
Gastrointestinal haemorrhage	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Haematemesis	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
General disorders
Generalised oedema	1/48 (2.1%)		0/89 (0%)		0/32 (0%)		0/58 (0%)
Pyrexia	1/48 (2.1%)		0/89 (0%)		1/32 (3.1%)		0/58 (0%)
Multiple Organ dysfunction syndrome	0/48 (0%)		0/89 (0%)		0/32 (0%)		1/58 (1.7%)
Hepatobiliary disorders
Chronic hepatic failure	0/48 (0%)		0/89 (0%)		0/32 (0%)		1/58 (1.7%)
Infections and infestations
Cellulitis	0/48 (0%)		0/89 (0%)		0/32 (0%)		1/58 (1.7%)
Clostridium difficile infection	0/48 (0%)		0/89 (0%)		0/32 (0%)		1/58 (1.7%)
Pneumonia	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Sepsis	0/48 (0%)		0/89 (0%)		0/32 (0%)		1/58 (1.7%)
Urinary tract infection	0/48 (0%)		0/89 (0%)		0/32 (0%)		1/58 (1.7%)
Injury, poisoning and procedural complications
Anaphylactic transfusion reaction	1/48 (2.1%)		0/89 (0%)		0/32 (0%)		0/58 (0%)
Post procedural haemorrhage	1/48 (2.1%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Procedural haemorrhage	1/48 (2.1%)		0/89 (0%)		0/32 (0%)		0/58 (0%)
Procedural pain	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Transfusion reaction	3/48 (6.3%)		0/89 (0%)		0/32 (0%)		0/58 (0%)
Investigations
Clostridium test positive	1/48 (2.1%)		0/89 (0%)		0/32 (0%)		0/58 (0%)
Platelet count decreased	1/48 (2.1%)		0/89 (0%)		0/32 (0%)		0/58 (0%)
Metabolism and nutrition disorders
Hyperkalaemia	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Hyponatraemia	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		1/58 (1.7%)
Musculoskeletal and connective tissue disorders
Muscle spasms	0/48 (0%)		0/89 (0%)		0/32 (0%)		1/58 (1.7%)
Myalgia	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Nervous system disorders
Coma hepatic	0/48 (0%)		0/89 (0%)		0/32 (0%)		1/58 (1.7%)
Hepatic encephalopathy	1/48 (2.1%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Syncope	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Renal and urinary disorders
Acute kidney injury	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Azotaemia	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/48 (2.1%)		0/89 (0%)		0/32 (0%)		0/58 (0%)
Vascular disorders
Hypotension	0/48 (0%)		1/89 (1.1%)		0/32 (0%)		0/58 (0%)
Other (Not Including Serious) Adverse Events
	60 mg Placebo (Lower Baseline Platelet Count)		60 mg Avatrombopag, (Lower Baseline Platelet Count)		40 mg Placebo (Higher Baseline Platelet Count)		40 mg Avatrombopag (Higher Baseline Platelet Count)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/48 (27.1%)		28/89 (31.5%)		9/32 (28.1%)		16/58 (27.6%)
Gastrointestinal disorders
Abdominal pain	3/48 (6.3%)		8/89 (9%)		3/32 (9.4%)		5/58 (8.6%)
Dyspepsia	2/48 (4.2%)		0/89 (0%)		2/32 (6.3%)		0/58 (0%)
Nausea	2/48 (4.2%)		4/89 (4.5%)		2/32 (6.3%)		5/58 (8.6%)
General disorders
Fatigue	1/48 (2.1%)		6/89 (6.7%)		1/32 (3.1%)		1/58 (1.7%)
Oedema peripheral	2/48 (4.2%)		3/89 (3.4%)		1/32 (3.1%)		3/58 (5.2%)
Pyrexia	5/48 (10.4%)		7/89 (7.9%)		1/32 (3.1%)		5/58 (8.6%)
Infections and infestations
Gastroenteritis	0/48 (0%)		0/89 (0%)		2/32 (6.3%)		0/58 (0%)
Injury, poisoning and procedural complications
Procedural pain	0/48 (0%)		6/89 (6.7%)		0/32 (0%)		0/58 (0%)
Nervous system disorders
Headache	3/48 (6.3%)		5/89 (5.6%)		2/32 (6.3%)		6/58 (10.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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