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

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

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.

Study Overview

• Status: Completed
• Conditions: Thrombocytopenia Related to Chronic Liver Disease
• Intervention / Treatment: Drug: Avatrombopag; Drug: Avatrombopag; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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
5. Subjects who are scheduled to undergo an elective invasive procedure between 1 to 4 days post last dose of study drug.
6. Adequate renal function as evidenced by a calculated creatinine clearance ≥50 mL/minute per the Cockcroft and Gault formula
7. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: Avatrombopag; Avatrombopag first Dose 80 mg followed by 10 mg a day for up to 6 additional days; Drug: Avatrombopag; Avatrombopag first Dose 80 mg followed by 20 mg a day for 3 days and then Placebo for 3 additional days
Experimental: 2	Drug: Avatrombopag; Avatrombopag first Dose 80 mg followed by 10 mg a day for up to 6 additional days; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Experiencing Response	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.	Day 8 (Visit 5, EOT)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Platelet Count on Day 8 (Visit 5 and/or End of Treatment) From Baseline	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.	Day 8 (Visit 5, EOT)
Percentage of Participants Experiencing Dose-response by Visit	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.	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)
Percentage of Participants Who Achieved a Platelet Count Greater Than 75,000/mm^3 on Day 4	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.	Day 4 (Visit 3)
Percentage of Participants Who Achieved a Platelet Count Greater Than 100,000/mm^3 on Days 4 and 8	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.	Day 4 (Visit 3) and Day 8 (Visit 5, EOT)

Collaborators and Investigators

• Sponsor: Eisai Inc.
• Investigators: Study Director: Tim Jenkins, Eisai Inc.

Study record dates

Study Major Dates

• Study Start: May 1, 2009
• Primary Completion (Actual): November 11, 2011
• Study Completion (Actual): December 21, 2011

Study Registration Dates

• First Submitted: June 4, 2009
• First Submitted That Met QC Criteria: June 4, 2009
• First Posted (Estimate): June 5, 2009

Study Record Updates

• Last Update Posted (Actual): January 23, 2018
• Last Update Submitted That Met QC Criteria: January 19, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Thrombocytopenia; chronic liver disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Hematologic Diseases; Blood Platelet Disorders; Liver Diseases; Thrombocytopenia
• Other Study ID Numbers: E5501-G000-202