Once-Daily Oral Avatrombopag Tablets Used in Subjects With Chronic Liver Diseases and Thrombocytopenia Prior to Elective Surgical or Diagnostic Procedures

• Sponsor: Eisai Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00914927
• Collaborator: (none)
• Enrollment: 130
• Location: 1
• Arms: 3
• Duration (Months): 31.7
• Patients Per Site Per Month: 4.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of once-daily Oral avatrombopagin subjects with chronic liver diseases and thrombocytopenia prior to elective surgical or diagnostic procedures, to evaluate the safety of short-term administration of avatrombopag and to evaluate the pharmacokinetics (PK) of E5501.

Condition or Disease	Intervention/Treatment	Phase
Thrombocytopenia Related to Chronic Liver Disease	Drug: Avatrombopag; Drug: Avatrombopag; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 130 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Multicenter, Placebo-Controlled, Double-Blind, Parallel-Group Study to Evaluate the Efficacy, Safety, and Population Pharmacokinetics of Once-Daily Oral E5501 Tablets Used Up to 7 Days in Subjects With Chronic Liver Diseases and Thrombocytopenia Prior to Elective Surgical or Diagnostic Procedures
• Study Start Date: May 1, 2009
• Actual Primary Completion Date: Nov 11, 2011
• Actual Study Completion Date: Dec 21, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: Avatrombopag; Avatrombopag first Dose 80 mg followed by 10 mg a day for up to 6 additional days
Experimental: 2	Drug: Avatrombopag; Avatrombopag first Dose 80 mg followed by 20 mg a day for 3 days and then Placebo for 3 additional days; Drug: Placebo; Placebo or inactive substance once a day for up to 7 days
Placebo Comparator: 3	Drug: Placebo; Placebo or inactive substance once a day for up to 7 days

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Experiencing Response [Day 8 (Visit 5, EOT)]

   Platelet counts (PC) were determined from blood draws. A responder is defined as a participant having an increase of at least 20,000/mm^3 PC from Baseline and a PC greater than 50,000/mm^3 at least once during Day 4 through Day 8. Missing PC assessments at any given time point was considered to be a non-response at that point and were not estimated. For PC measurements taken after the last dose day (end of treatment (EOT)), the postdose windows applied. If there was more than one PC within the same analysis visit window, the following selection rules were applied sequentially to determine which PC was used for that time point: 1) the PC that was closer to the target date was used, 2) if PC were equal-distance in days from the target day, the later one based on measurement date and time was used, and 3) if there was more than one PC on the same day, if it was a baseline record, the largest one was used; if it was a postbaseline record, the smallest one was used.

Secondary Outcome Measures

1. Change in Platelet Count on Day 8 (Visit 5 and/or End of Treatment) From Baseline [Day 8 (Visit 5, EOT)]

   Platelet counts were determined from blood draws. Missing PC assessments at any given time point was considered to be a non-response at that point and were not estimated. For PC measurements taken after the last dose day (EOT), the postdose windows applied. If there was more than one PC within the same analysis visit window, the following selection rules were applied sequentially to determine which PC was used for that time point: 1) the PC that was closer to the target date was used, 2) if PC were equal-distance in days from the target day, the later one based on measurement date and time was used, and 3) if there was more than one PC on the same day, if it was a baseline record, the largest one was used; if it was a postbaseline record, the smallest one was used.

2. Percentage of Participants Experiencing Dose-response by Visit [Day 4 (Visit 3), Day 6 ( Visit 4), Day 8 (Visit 5, EOT), 3 Day Post Last Dose (Visit 6), and 7 Day Post Last Dose (Visit 7)]

   Platelet counts were determined from blood draws. Missing PC assessments at any given time point was considered to be a non-response at that point and were not estimated. For PC measurements taken after the last dose day (EOT), the postdose windows applied. If there was more than one PC within the same analysis visit window, the following selection rules were applied sequentially to determine which PC was used for that time point: 1) the PC that was closer to the target date was used, 2) if PC were equal-distance in days from the target day, the later one based on measurement date and time was used, and 3) if there was more than one PC on the same day, if it was a baseline record, the largest one was used; if it was a postbaseline record, the smallest one was used.

3. Percentage of Participants Who Achieved a Platelet Count Greater Than 75,000/mm^3 on Day 4 [Day 4 (Visit 3)]

   Platelet counts were determined from blood draws. Missing PC assessments at any given time point was considered to be a non-response at that point and were not estimated. For PC measurements taken after the last dose day (EOT), the postdose windows applied. If there was more than one PC within the same analysis visit window, the following selection rules were applied sequentially to determine which PC was used for that time point: 1) the PC that was closer to the target date was used, 2) if PC were equal-distance in days from the target day, the later one based on measurement date and time was used, and 3) if there was more than one PC on the same day, if it was a baseline record, the largest one was used; if it was a postbaseline record, the smallest one was used.

4. Percentage of Participants Who Achieved a Platelet Count Greater Than 100,000/mm^3 on Days 4 and 8 [Day 4 (Visit 3) and Day 8 (Visit 5, EOT)]

   Platelet counts were determined from blood draws. Missing PC assessments at any given time point was considered to be a non-response at that point and were not estimated. For PC measurements taken after the last dose day (EOT), the postdose windows applied. If there was more than one PC within the same analysis visit window, the following selection rules were applied sequentially to determine which PC was used for that time point: 1) the PC that was closer to the target date was used, 2) if PC were equal-distance in days from the target day, the later one based on measurement date and time was used, and 3) if there was more than one PC on the same day, if it was a baseline record, the largest one was used; if it was a postbaseline record, the smallest one was used.

Eligibility Criteria

Criteria

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

Key Inclusion Criteria:

1. Males or females ≥ 18 years of age

2. Thrombocytopenia (defined as a platelet count ≥ 10,000 - ≤ 50,000 (+15%)/mm^3 )

3. Model for End-Stage Liver Disease (MELD) scores ≤ 24

4. Chronic liver diseases due to one of the following three etiologies:

Chronic Viral Hepatitis from one of the following categories

• Chronic Hepatitis C (defined as the presence of anti-hepatitis C virus [HCV] antibodies and/or detectable serum HCV ribonucleic acid [RNA] levels)

• OR chronic Hepatitis B (defined as the presence of hepatitis B surface antigen [HBsAg] and/or detectable serum hepatitis B virus [HBV] deoxyribonucleic acid [DNA])

• OR chronic Hepatitis B and C co-infection (as defined by the above bullet points)

• OR chronic Hepatitis C and history of alcohol abuse

• OR chronic Hepatitis B and history of alcohol abuse

NASH diagnosed as:

• absence of serologic evidence of viral hepatitis and

• convincing evidence of a history of minimal or no alcohol consumption, and

• histologic picture of steatohepatitis OR

• when histology is unavailable, then clinical, radiographic and laboratory evidence of NASH

Alcoholic liver disease diagnosed as:

• absence of serologic evidence of viral hepatitis and

• history of heavy alcohol consumption and

• histologic picture of alcoholic liver disease OR

• when histology is unavailable, then clinical, radiographic and laboratory evidence of hepatitis combined with years of excessive alcohol intake

1. Subjects who are scheduled to undergo an elective invasive procedure between 1 to 4 days post last dose of study drug.

2. Adequate renal function as evidenced by a calculated creatinine clearance ≥50 mL/minute per the Cockcroft and Gault formula

3. Life expectancy ≥3 months

Key Exclusion Criteria:

1. Hepatic encephalopathy that cannot be effectively treated.

2. Platelet transfusion within 7 days prior to the first dose of study drug

3. Received blood products, eg, FFP and cryoprecipitate 7 days prior to the first dose of study drug

4. Have surgical or diagnostic procedure scheduled during the Randomization Phase (Day 1 to Day 8) of this study

5. Interferon use within 2 weeks of Day 1

6. Hormonal contraceptive use within 60 days of study entry

7. History of human immunodeficiency virus (HIV) infection

8. Any prohibited concomitant medications or therapy that cannot be discontinued by Visit 1

9. Active alcohol abuse, active alcohol dependence syndrome, drug abuse, or drug dependence within 6 months of the study start (unless participating in a controlled rehabilitation program)

10. Acute alcoholic hepatitis (chronic alcoholic hepatitis is allowed) within 6 months of the study start

11. History of any primary hematologic disorder

12. History of arterial or venous thrombosis, including thrombosis of any part of the splenic-mesenteric system

13. Any evidence of current portal vein thrombosis (PVT) as detected by Doppler sonography or appropriate MRI/CT imaging at Screening and/or within approximately 30 days prior to Screening

14. Any acute/active bleeding (gastrointestinal [GI], central nervous system [CNS], etc)

15. Uncompensated congestive heart failure (New York Heart Association [NYHA] Class III or IV)

16. Pre-diagnosed Immune Thrombocytopenic Purpura (ITP)

17. History of Myelodysplastic Syndrome (MDS)

18. Females who are pregnant (positive β-hCG test ) or breastfeeding

19. Current use of recreational drugs

20. Post-transplant patients

21. Subjects who have participated in another investigational trial within 30 days prior to Visit 1.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121

Sponsors and Collaborators

• Eisai Inc.

Investigators

• Study Director: Tim Jenkins, Eisai Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT00914927
• Other Study ID Numbers: E5501-G000-202
• First Posted: Jun 5, 2009
• Last Update Posted: Jan 23, 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

Arm/Group Title	Cohort A: 20 mg Avatrombopag, 1G Formulation	Cohort A: 40 mg Avatrombopag, 1G Formulation	Cohort A: 80 mg Avatrombopag, 1G Formulation	Cohort A: Placebo, 1G Formulation	Cohort B: 0 mg Avatrombopag, 2G Formulation	Cohort B: 20 mg Avatrombopag, 2G Formulation	Cohort B: Placebo, 2G Formulation
Arm/Group Description	Participants received a 100 mg loading dose of the first generation (1G) formulation avatrombopag on Day 1, followed by 20 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 40 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 80 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received the 1G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.	Participants received an 80 mg loading dose of the second generation (2G) formulation avatrombopag on Day 1, followed by 10 mg 2G formulation avatrombopag once daily on Days 2 to 7.	Participants received an 80 mg loading dose of the 2G formulation avatrombopag on Day 1, followed by 20 mg 2G formulation avatrombopag once daily on Days 2 to 4 followed by 2G avatrombopag-matched placebo once daily on Days 5 to 7.	Participants received the 2G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.
Period Title: Overall Study
STARTED	18	16	17	16	21	21	21
COMPLETED	16	14	17	14	19	21	21
NOT COMPLETED	2	2	0	2	2	0	0

Baseline Characteristics

Arm/Group Title	Cohort A: 20 mg Avatrombopag, 1G Formulation	Cohort A: 40 mg Avatrombopag, 1G Formulation	Cohort A: 80 mg Avatrombopag, 1G Formulation	Cohort A: Placebo, 1G Formulation	Cohort B: 10 mg Avatrombopag, 2G Formulation	Cohort B: 20 mg Avatrombopag, 2G Formulation	Cohort B: Placebo, 2G Formulation	Total
Arm/Group Description	Participants received a 100 mg loading dose of the first generation (1G) formulation avatrombopag on Day 1, followed by 20 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 40 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 80 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received the 1G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.	Participants received an 80 mg loading dose of the second generation (2G) formulation avatrombopag on Day 1, followed by 10 mg 2G formulation avatrombopag once daily on Days 2 to 7.	Participants received an 80 mg loading dose of the 2G formulation avatrombopag on Day 1, followed by 20 mg 2G formulation avatrombopag once daily on Days 2 to 4 followed by 2G avatrombopag-matched placebo once daily on Days 5 to 7.	Participants received the 2G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.	Total of all reporting groups
Overall Participants	18	16	17	16	21	21	21	130
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55.3 (7.16)	52.8 (7.78)	55.2 (5.96)	54.2 (6.87)	53.9 (5.48)	56.8 (6.46)	55.6 (6.52)	54.8 (6.56)
Sex: Female, Male (Count of Participants)
Female	4 22.2%	3 18.8%	6 35.3%	5 31.3%	10 47.6%	7 33.3%	7 33.3%	42 32.3%
Male	14 77.8%	13 81.3%	11 64.7%	11 68.8%	11 52.4%	14 66.7%	14 66.7%	88 67.7%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Experiencing Response
Description	Platelet counts (PC) were determined from blood draws. A responder is defined as a participant having an increase of at least 20,000/mm^3 PC from Baseline and a PC greater than 50,000/mm^3 at least once during Day 4 through Day 8. Missing PC assessments at any given time point was considered to be a non-response at that point and were not estimated. For PC measurements taken after the last dose day (end of treatment (EOT)), the postdose windows applied. If there was more than one PC within the same analysis visit window, the following selection rules were applied sequentially to determine which PC was used for that time point: 1) the PC that was closer to the target date was used, 2) if PC were equal-distance in days from the target day, the later one based on measurement date and time was used, and 3) if there was more than one PC on the same day, if it was a baseline record, the largest one was used; if it was a postbaseline record, the smallest one was used.
Time Frame	Day 8 (Visit 5, EOT)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population included all participants who were randomized into the study, received study medication, and had a posttreatment assessment. The ITT population was analyzed as randomized.

Arm/Group Title	Cohort A: 20 mg Avatrombopag, 1G Formulation	Cohort A: 40 mg Avatrombopag , 1G Formulation	Cohort A: 80 mg Avatrombopag, 1G Formulation	Cohort A: Placebo, 1G Formulation	Cohort B:10 mg Avatrombopag, 2G Formulation	Cohort B: 20 mg Avatrombopag, 2G Formulation	Cohort B: Placebo, 2G Formulation
Arm/Group Description	Participants received a 100 mg loading dose of the first generation (1G) formulation avatrombopag on Day 1, followed by 20 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 40 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 80 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received the 1G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.	Participants received the 1G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.	Participants received an 80 mg loading dose of the 2G formulation avatrombopag on Day 1, followed by 20 mg 2G formulation avatrombopag once daily on Days 2 to 4 followed by 2G avatrombopag-matched placebo once daily on Days 5 to 7.	Participants received the 2G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.
Measure Participants	18	16	17	16	21	21	21
Yes response	38.9 216.1%	31.3 195.6%	76.5 450%	6.3 39.4%	42.9 204.3%	52.4 249.5%	9.5 45.2%
No response	61.1 339.4%	68.8 430%	23.5 138.2%	93.8 586.3%	57.1 271.9%	47.6 226.7%	90.5 431%

2. Secondary Outcome

Title	Change in Platelet Count on Day 8 (Visit 5 and/or End of Treatment) From Baseline
Description	Platelet counts were determined from blood draws. Missing PC assessments at any given time point was considered to be a non-response at that point and were not estimated. For PC measurements taken after the last dose day (EOT), the postdose windows applied. If there was more than one PC within the same analysis visit window, the following selection rules were applied sequentially to determine which PC was used for that time point: 1) the PC that was closer to the target date was used, 2) if PC were equal-distance in days from the target day, the later one based on measurement date and time was used, and 3) if there was more than one PC on the same day, if it was a baseline record, the largest one was used; if it was a postbaseline record, the smallest one was used.
Time Frame	Day 8 (Visit 5, EOT)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all participants who were randomized into the study, received study medication, and had a posttreatment assessment. The ITT population was analyzed as randomized.

Arm/Group Title	Cohort A: 20 mg Aavatrombopag, 1G Formulation	Cohort A: 40 mg Avatrombopag, 1G Formulation	Cohort A: 80 mg Avatrombopag, 1G Formulation	Cohort A: Placebo, 1G Formulation	Cohort B: 10 mg Avatrombopag, 2G Formulation	Cohort B: 20 mg Aavatrombopag, 2G Formulation	Cohort B: Placebo, 2G Formulation
Arm/Group Description	Participants received a 100 mg loading dose of the first generation (1G) formulation avatrombopag on Day 1, followed by 20 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 40 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 80 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received the 1G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.	Participants received an 80 mg loading dose of the second generation (2G) formulation avatrombopag on Day 1, followed by 10 mg 2G formulation avatrombopag once daily on Days 2 to 7.	Participants received an 80 mg loading dose of the 2G formulation avatrombopag on Day 1, followed by 20 mg 2G formulation avatrombopag once daily on Days 2 to 4 followed by 2G avatrombopag-matched placebo once daily on Days 5 to 7.	Participants received the 2G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.
Measure Participants	18	16	17	16	21	21	21
Mean (Standard Deviation) [K/mm^3]	16.2 (10.32)	15.9 (13.45)	32.2 (18.59)	3.1 (17.97)	18.9 (10.07)	24.9 (17.91)	3.9 (12.49)

3. Secondary Outcome

Title	Percentage of Participants Experiencing Dose-response by Visit
Description	Platelet counts were determined from blood draws. Missing PC assessments at any given time point was considered to be a non-response at that point and were not estimated. For PC measurements taken after the last dose day (EOT), the postdose windows applied. If there was more than one PC within the same analysis visit window, the following selection rules were applied sequentially to determine which PC was used for that time point: 1) the PC that was closer to the target date was used, 2) if PC were equal-distance in days from the target day, the later one based on measurement date and time was used, and 3) if there was more than one PC on the same day, if it was a baseline record, the largest one was used; if it was a postbaseline record, the smallest one was used.
Time Frame	Day 4 (Visit 3), Day 6 ( Visit 4), Day 8 (Visit 5, EOT), 3 Day Post Last Dose (Visit 6), and 7 Day Post Last Dose (Visit 7)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all participants who were randomized into the study, received study medication, and had a posttreatment assessment. The ITT population was analyzed as randomized.

Arm/Group Title	Cohort A: 20 mg Avatrombopag, 1G Formulation	Cohort A:40 mg Avatrombopag, 1G Formulation	Cohort A: 80 mg Avatrombopag, 1G Formulation	Cohort A: Placebo, 1G Formulation	Cohort B: 10 mg Avatrombopag, 2G Formulation	Cohort B: 20 mg Avatrombopag, 2G Formulation	Cohort B: Placebo, 2G Formulation
Arm/Group Description	Participants received a 100 mg loading dose of the first generation (1G) formulation avatrombopag on Day 1, followed by 20 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 40 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 80 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received the 1G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.	Participants received an 80 mg loading dose of the second generation (2G) formulation avatrombopag on Day 1, followed by 10 mg 2G formulation avatrombopag once daily on Days 2 to 7.	Participants received an 80 mg loading dose of the 2G formulation avatrombopag on Day 1, followed by 20 mg 2G formulation avatrombopag once daily on Days 2 to 4 followed by 2G avatrombopag-matched placebo once daily on Days 5 to 7.	Participants received the 2G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.
Measure Participants	18	16	17	16	21	21	21
Yes response (Day 4, Visit 3)	0 0%	0 0%	5.9 34.7%	0 0%	0 0%	4.8 22.9%	4.8 22.9%
No response (Day 4, Visit 3)	100.0 555.6%	100.0 625%	94.1 553.5%	100.0 625%	100.0 476.2%	95.2 453.3%	95.2 453.3%
Yes response (Day 6, Visit 4)	11.1 61.7%	12.5 78.1%	29.4 172.9%	0 0%	14.3 68.1%	33.3 158.6%	9.5 45.2%
No response (Day 6, Visit 4)	88.9 493.9%	87.5 546.9%	70.6 415.3%	100.0 625%	85.7 408.1%	66.7 317.6%	90.5 431%
Yes response (Day 8, Visit 5)	38.9 216.1%	31.3 195.6%	76.5 450%	6.3 39.4%	42.9 204.3%	52.4 249.5%	9.5 45.2%
No response (Day 8, Visit 5)	61.1 339.4%	68.8 430%	23.5 138.2%	93.8 586.3%	57.1 271.9%	47.6 226.7%	90.5 431%
Yes response (3 Day post last dose, Visit 6)	55.6 308.9%	56.3 351.9%	82.4 484.7%	12.5 78.1%	66.7 317.6%	61.9 294.8%	9.5 45.2%
No response (3 Day post last dose, Visit 6)	44.4 246.7%	43.8 273.8%	17.6 103.5%	87.5 546.9%	33.3 158.6%	38.1 181.4%	90.5 431%
Yes response (7 Day post last dose, Visit 7)	61.1 339.4%	62.5 390.6%	88.2 518.8%	12.5 78.1%	71.4 340%	61.9 294.8%	9.5 45.2%
No response (7 Day post last dose, Visit 7)	38.9 216.1%	37.5 234.4%	11.8 69.4%	87.5 546.9%	28.6 136.2%	38.1 181.4%	90.5 431%

4. Secondary Outcome

Title	Percentage of Participants Who Achieved a Platelet Count Greater Than 75,000/mm^3 on Day 4
Description	Platelet counts were determined from blood draws. Missing PC assessments at any given time point was considered to be a non-response at that point and were not estimated. For PC measurements taken after the last dose day (EOT), the postdose windows applied. If there was more than one PC within the same analysis visit window, the following selection rules were applied sequentially to determine which PC was used for that time point: 1) the PC that was closer to the target date was used, 2) if PC were equal-distance in days from the target day, the later one based on measurement date and time was used, and 3) if there was more than one PC on the same day, if it was a baseline record, the largest one was used; if it was a postbaseline record, the smallest one was used.
Time Frame	Day 4 (Visit 3)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all participants who were randomized into the study, received study medication, and had a posttreatment assessment. The ITT population was analyzed as randomized.

Arm/Group Title	Cohort A: 20 mg Avatrombopag, IG Formulation	Cohort A: 40 mg Avatrombopag, IG Formulation	Cohort A: 80 mg Avatrombopag, IG Formulation	Cohort A: Placebo, IG Formulation	Cohort B: 10 mg Avatrombopag, 2G Formulation	Cohort B: 20 mg Avatrombopag, 2G Formulation	Cohort B: Placebo, 2G Formulation
Arm/Group Description	Participants received a 100 mg loading dose of the first generation (1G) formulation avatrombopag on Day 1, followed by 20 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 40 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 80 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received the 1G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.	Participants received an 80 mg loading dose of the second generation (2G) formulation avatrombopag on Day 1, followed by 10 mg 2G formulation avatrombopag once daily on Days 2 to 7.	Participants received an 80 mg loading dose of the 2G formulation avatrombopag on Day 1, followed by 20 mg 2G formulation avatrombopag once daily on Days 2 to 4 followed by 2G avatrombopag-matched placebo once daily on Days 5 to 7.	Participants received the 2G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.
Measure Participants	18	16	17	16	21	21	21
Yes response	5.6 31.1%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No response	94.4 524.4%	100.0 625%	100.0 588.2%	100.0 625%	100.0 476.2%	100.0 476.2%	100.0 476.2%

5. Secondary Outcome

Title	Percentage of Participants Who Achieved a Platelet Count Greater Than 100,000/mm^3 on Days 4 and 8
Description	Platelet counts were determined from blood draws. Missing PC assessments at any given time point was considered to be a non-response at that point and were not estimated. For PC measurements taken after the last dose day (EOT), the postdose windows applied. If there was more than one PC within the same analysis visit window, the following selection rules were applied sequentially to determine which PC was used for that time point: 1) the PC that was closer to the target date was used, 2) if PC were equal-distance in days from the target day, the later one based on measurement date and time was used, and 3) if there was more than one PC on the same day, if it was a baseline record, the largest one was used; if it was a postbaseline record, the smallest one was used.
Time Frame	Day 4 (Visit 3) and Day 8 (Visit 5, EOT)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all participants who were randomized into the study, received study medication, and had a posttreatment assessment. The ITT population was analyzed as randomized.

Arm/Group Title	Cohort A: 20 mg Avatrombopag, 1G Formulation	Cohort A: 40 mg Avatrombopag, 1G Formulation	Cohort A: 80 mg Avatrombopag, 1G Formulation	Cohort A: Placebo, 1G Formulation	Cohort B: 10 mg Avatrombopag, 2G Formulation	Cohort B: 20 mg Avatrombopag, 2G Formulation	Cohort B: Placebo, 2G Formulation
Arm/Group Description	Participants received a 100 mg loading dose of the first generation (1G) formulation avatrombopag on Day 1, followed by 20 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 40 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 80 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.	Participants received the 1G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.	Participants received an 80 mg loading dose of the second generation (2G) formulation avatrombopag on Day 1, followed by 10 mg 2G formulation avatrombopag once daily on Days 2 to 7.	Participants received an 80 mg loading dose of the 2G formulation avatrombopag on Day 1, followed by 20 mg 2G formulation avatrombopag once daily on Days 2 to 4 followed by 2G avatrombopag-matched placebo once daily on Days 5 to 7.	Participants received the 2G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.
Measure Participants	18	16	17	16	21	21	21
Yes response (Day 4, Visit 3)	5.6 31.1%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
No response (Day 4, Visit 3)	94.4 524.4%	100.0 625%	100.0 588.2%	100.0 625%	100.0 476.2%	100.0 476.2%	100.0 476.2%
Yes response (Day 8, Visit 5)	5.6 31.1%	0 0%	11.8 69.4%	0 0%	4.8 22.9%	9.5 45.2%	0 0%
No response (Day 8, Visit 5)	94.4 524.4%	100.0 625%	88.2 518.8%	100.0 625%	95.2 453.3%	90.5 431%	100.0 476.2%

Adverse Events

Time Frame	Approximately 44 days.
Adverse Event Reporting Description	Treatment-emergent adverse events and treatment-emergent serious adverse events were reported. The safety population included all randomized participants who received at least one dose of study drug and had a postbaseline safety assessment. The safety population was analyzed as treated.
Arm/Group Title	Cohort A: 20 mg Avatrombopag, 1G Formulation		Cohort A: 40 mg Avatrombopag, 1G Formulation		Cohort A: 80 mg Avatrombopag, 1G Formulation		Cohort A: Placebo, 1G Formulation		Cohort B: 10 mg Avatrombopag, 2G Formulation		Cohort B: 20 mg Avatrombopag, 2G Formulation		Cohort B: Placebo, 2G Formulation
Arm/Group Description	Participants received a 100 mg loading dose of the first generation (1G) formulation avatrombopag on Day 1, followed by 20 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.		Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 40 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.		Participants received a 100 mg loading dose of the 1G formulation avatrombopag on Day 1, followed by 80 mg of the 1G formulation avatrombopag once daily on Days 2 to 7.		Participants received the 1G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.		Participants received an 80 mg loading dose of the second generation (2G) formulation avatrombopag on Day 1, followed by 10 mg 2G formulation avatrombopag once daily on Days 2 to 7.		Participants received an 80 mg loading dose of the 2G formulation avatrombopag on Day 1, followed by 20 mg 2G formulation avatrombopag once daily on Days 2 to 4 followed by 2G avatrombopag-matched placebo once daily on Days 5 to 7.		Participants received the 2G formulation avatrombopag-matched placebo loading dose on Day 1, then once daily on Days 2 to 7.
All Cause Mortality
	Cohort A: 20 mg Avatrombopag, 1G Formulation		Cohort A: 40 mg Avatrombopag, 1G Formulation		Cohort A: 80 mg Avatrombopag, 1G Formulation		Cohort A: Placebo, 1G Formulation		Cohort B: 10 mg Avatrombopag, 2G Formulation		Cohort B: 20 mg Avatrombopag, 2G Formulation		Cohort B: Placebo, 2G Formulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Serious Adverse Events
	Cohort A: 20 mg Avatrombopag, 1G Formulation		Cohort A: 40 mg Avatrombopag, 1G Formulation		Cohort A: 80 mg Avatrombopag, 1G Formulation		Cohort A: Placebo, 1G Formulation		Cohort B: 10 mg Avatrombopag, 2G Formulation		Cohort B: 20 mg Avatrombopag, 2G Formulation		Cohort B: Placebo, 2G Formulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/18 (16.7%)		2/16 (12.5%)		3/17 (17.6%)		1/16 (6.3%)		5/21 (23.8%)		3/21 (14.3%)		3/21 (14.3%)
Blood and lymphatic system disorders
Anaemia	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Cardiac disorders
Cardio-respiratory arrest	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Gastrointestinal disorders
Gastric haemorrhage	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Upper gastrointestinal haemorrhage	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Abdominal pain	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Ascites	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		1/21 (4.8%)
Heamorrhoidal haemorrhage	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		1/21 (4.8%)		0/21 (0%)
Hepatobiliary disorders
Liver disorder	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Portal vein thrombosis	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Infections and infestations
Cellulitis	0/18 (0%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Pneumonia	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Peritonitis bacterial	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		1/21 (4.8%)		1/21 (4.8%)
Staphylcoccal abscess	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Injury, poisoning and procedural complications
Intentional overdose	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Seroma	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Fall	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Metabolism and nutrition disorders
Metabolic acidosis	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Musculoskeletal and connective tissue disorders
Muscular weakness	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		1/21 (4.8%)		0/21 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tongue neoplasm malignant stage unspecified	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Nervous system disorders
Hepatic encephalopathy	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		1/21 (4.8%)
Hypoaesthesia	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		1/21 (4.8%)		0/21 (0%)
Psychiatric disorders
Suicidal ideation	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		1/21 (4.8%)		0/21 (0%)
Renal and urinary disorders
Acute prerenal failure	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Renal failure acute	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Acute respiratory failure	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Cohort A: 20 mg Avatrombopag, 1G Formulation		Cohort A: 40 mg Avatrombopag, 1G Formulation		Cohort A: 80 mg Avatrombopag, 1G Formulation		Cohort A: Placebo, 1G Formulation		Cohort B: 10 mg Avatrombopag, 2G Formulation		Cohort B: 20 mg Avatrombopag, 2G Formulation		Cohort B: Placebo, 2G Formulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/18 (94.4%)		13/16 (81.3%)		13/17 (76.5%)		12/16 (75%)		17/21 (81%)		18/21 (85.7%)		16/21 (76.2%)
Blood and lymphatic system disorders
Anaemia	1/18 (5.6%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Coagulopathy	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Lymphadenopathy	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		2/21 (9.5%)
Cardiac disorders
Bradycardia	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Cardiomegaly	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		1/21 (4.8%)
Mitral valve incompetence	0/18 (0%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		0/21 (0%)		1/21 (4.8%)
Tachycardia	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Pulmonary valve incompetence	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		2/21 (9.5%)
Tricuspid valve incompetence	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		2/21 (9.5%)
Ear and labyrinth disorders
Ear pain	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Eye disorders
Visual impairment	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Ocular icterus	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		2/21 (9.5%)		0/21 (0%)
Gastrointestinal disorders
Abdominal discomfort	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Abdominal distension	1/18 (5.6%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		1/21 (4.8%)		0/21 (0%)
Abdominal pain	1/18 (5.6%)		1/16 (6.3%)		0/17 (0%)		1/16 (6.3%)		2/21 (9.5%)		0/21 (0%)		3/21 (14.3%)
Abdominal pain upper	4/18 (22.2%)		1/16 (6.3%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Ascites	1/18 (5.6%)		1/16 (6.3%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		1/21 (4.8%)		3/21 (14.3%)
Colonic polyp	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		1/21 (4.8%)		0/21 (0%)
Constipation	2/18 (11.1%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		1/21 (4.8%)
Diarrhoea	2/18 (11.1%)		1/16 (6.3%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		3/21 (14.3%)		2/21 (9.5%)
Diverticulum intestinal	0/18 (0%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Dry mouth	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Dyspepsia	1/18 (5.6%)		1/16 (6.3%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		1/21 (4.8%)
Erosive duodenitis	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		1/21 (4.8%)
Frequent bowel movements	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Gastric haemorrhage	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Gastric polyps	1/18 (5.6%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		1/21 (4.8%)		1/21 (4.8%)		0/21 (0%)
Gastric verices	1/18 (5.6%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		2/21 (9.5%)		0/21 (0%)		1/21 (4.8%)
Gastritis	0/18 (0%)		0/16 (0%)		2/17 (11.8%)		0/16 (0%)		0/21 (0%)		1/21 (4.8%)		1/21 (4.8%)
Haemorrhoids	0/18 (0%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		1/21 (4.8%)		1/21 (4.8%)		0/21 (0%)
Hiatus hernia	0/18 (0%)		2/16 (12.5%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		2/21 (9.5%)		1/21 (4.8%)
Intestinal obstruction	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Intestinal polyp	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Nausea	1/18 (5.6%)		2/16 (12.5%)		2/17 (11.8%)		2/16 (12.5%)		5/21 (23.8%)		2/21 (9.5%)		3/21 (14.3%)
Odynophagia	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Oesophageal mass	0/18 (0%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Oesophagitis	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Oral pain	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Pancreatitis	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Polyp colorectal	0/18 (0%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Portal hypertensive gastropathy	4/18 (22.2%)		2/16 (12.5%)		0/17 (0%)		0/16 (0%)		3/21 (14.3%)		0/21 (0%)		2/21 (9.5%)
Upper gastrointestinal haemorrhage	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Varices oesophageal	2/18 (11.1%)		2/16 (12.5%)		0/17 (0%)		1/16 (6.3%)		1/21 (4.8%)		2/21 (9.5%)		0/21 (0%)
Vomiting	1/18 (5.6%)		2/16 (12.5%)		3/17 (17.6%)		0/16 (0%)		0/21 (0%)		1/21 (4.8%)		1/21 (4.8%)
Duodenal ulcer	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		2/21 (9.5%)		0/21 (0%)		0/21 (0%)
Faeces discolored	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		2/21 (9.5%)
Gastrooesophageal reflux disease	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		2/21 (9.5%)		0/21 (0%)
Gingival bleeding	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		2/21 (9.5%)
Rectal haemorrhage	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		3/21 (14.3%)		0/21 (0%)		0/21 (0%)
General disorders
Chills	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		1/21 (4.8%)		0/21 (0%)
Fatigue	4/18 (22.2%)		1/16 (6.3%)		0/17 (0%)		1/16 (6.3%)		2/21 (9.5%)		2/21 (9.5%)		4/21 (19%)
Hyperthermia	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Irritability	0/18 (0%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Malaise	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Non-cardiac chest pain	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Oedema peripheral	0/18 (0%)		1/16 (6.3%)		2/17 (11.8%)		0/16 (0%)		2/21 (9.5%)		0/21 (0%)		0/21 (0%)
Pyrexia	0/18 (0%)		0/16 (0%)		2/17 (11.8%)		2/16 (12.5%)		1/21 (4.8%)		0/21 (0%)		3/21 (14.3%)
Hepatobiliary disorders
Liver disorder	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Portal vein thrombosis	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Infections and infestations
Bronchitis	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		2/21 (9.5%)		0/21 (0%)		0/21 (0%)
Cellulitis	0/18 (0%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		1/21 (4.8%)		0/21 (0%)		1/21 (4.8%)
Fungal skin infection	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Helicobacter infection	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Localised infection	0/18 (0%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Nasopharyngitis	0/18 (0%)		0/16 (0%)		2/17 (11.8%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Oral herpes	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Pneumonia	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Sinusitus	0/18 (0%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Staphylococcal skin infection	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Upper respiratory tract infection	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		1/21 (4.8%)		1/21 (4.8%)		0/21 (0%)
Urinary tract infection	0/18 (0%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Vulvovaginal mycotic infection	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Injury, poisoning and procedural complications
Arthropid bite	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Clavicle fracture	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Contusion	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		0/21 (0%)		1/21 (4.8%)
Intentional overdose	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Iris injury	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Joint sprain	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Laceration	1/18 (5.6%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Post procedural haemorrhage	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Procedural pain	1/18 (5.6%)		2/16 (12.5%)		2/17 (11.8%)		0/16 (0%)		1/21 (4.8%)		1/21 (4.8%)		2/21 (9.5%)
Scratch	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Seroma	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Thermal burn	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Investigations
Blood creatinine increased	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		1/21 (4.8%)
Blood glucose increased	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Blood urine present	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Electrocardiogram T wave peaked	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Glucose urine present	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Heart rate increased	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Urine output decreased	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Weight increased	0/18 (0%)		2/16 (12.5%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Haemoglobin decreased	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		2/21 (9.5%)
Metabolism and nutrition disorders
Dehydration	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Hyperglycaemia	0/18 (0%)		2/16 (12.5%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Hyperkalaemia	2/18 (11.1%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Hypokalaemia	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		1/21 (4.8%)
Hyponatraemia	2/18 (11.1%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Hypophosphataemia	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Musculoskeletal and connective tissue disorders
Muscle spasms	1/18 (5.6%)		1/16 (6.3%)		2/17 (11.8%)		0/16 (0%)		2/21 (9.5%)		1/21 (4.8%)		1/21 (4.8%)
Muscular weakness	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		1/21 (4.8%)		0/21 (0%)
Musculoskeletal pain	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Myalgia	2/18 (11.1%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Pain in extremity	1/18 (5.6%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lipoma	2/18 (11.1%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Nervous system disorders
Dizziness	2/18 (11.1%)		0/16 (0%)		1/17 (5.9%)		1/16 (6.3%)		3/21 (14.3%)		1/21 (4.8%)		1/21 (4.8%)
Dysgeusia	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Headache	2/18 (11.1%)		2/16 (12.5%)		1/17 (5.9%)		2/16 (12.5%)		1/21 (4.8%)		3/21 (14.3%)		3/21 (14.3%)
Hepatic encephalopathy	2/18 (11.1%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		1/21 (4.8%)
Paraesthesia	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Sinus headache	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Somnolence	0/18 (0%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		1/21 (4.8%)		0/21 (0%)
Unresponsive to stimuli	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Hypoaesthesia	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		2/21 (9.5%)		0/21 (0%)
Psychiatric disorders
Depressed mood	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Depression	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Insomnia	1/18 (5.6%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		1/21 (4.8%)		1/21 (4.8%)		1/21 (4.8%)
Listless	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		1/21 (4.8%)		0/21 (0%)
Mental status change	0/18 (0%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Restlessness	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Renal and urinary disorders
Acute prerenal failure	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Pollakiuria	0/18 (0%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Polyuria	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Renal failure acute	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		1/21 (4.8%)		0/21 (0%)
Reproductive system and breast disorders
Erectile dysfunction	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Pelvic pain	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Scrotal swelling	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		1/21 (4.8%)
Epistaxis	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		1/21 (4.8%)		0/21 (0%)		1/21 (4.8%)
Hypoxia	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		1/21 (4.8%)
Nasal congestion	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Oropharyngeal pain	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		1/21 (4.8%)		0/21 (0%)
Painful respiration	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Pleural effusion	2/18 (11.1%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Rhinorrhoea	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Tachypnoea	0/18 (0%)		1/16 (6.3%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Wheezing	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Cough	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		2/21 (9.5%)		0/21 (0%)		2/21 (9.5%)
Haemoptysis	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		2/21 (9.5%)		0/21 (0%)		0/21 (0%)
Skin and subcutaneous tissue disorders
Ecchymosis	0/18 (0%)		1/16 (6.3%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Night sweats	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		0/21 (0%)		0/21 (0%)		0/21 (0%)
Petechiae	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		0/21 (0%)		1/21 (4.8%)
Pruritus	1/18 (5.6%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		1/21 (4.8%)
Rash	2/18 (11.1%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		1/21 (4.8%)		1/21 (4.8%)		1/21 (4.8%)
Vascular disorders
Hypertension	0/18 (0%)		0/16 (0%)		1/17 (5.9%)		0/16 (0%)		1/21 (4.8%)		0/21 (0%)		0/21 (0%)
Hypotension	1/18 (5.6%)		0/16 (0%)		0/17 (0%)		1/16 (6.3%)		0/21 (0%)		0/21 (0%)		1/21 (4.8%)
Aortic arteriosclerosis	0/18 (0%)		0/16 (0%)		0/17 (0%)		0/16 (0%)		2/21 (9.5%)		0/21 (0%)		0/21 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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