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

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ClinicalTrials.gov Identifier: NCT01972529
Recruitment Status : Completed
First Posted : October 30, 2013
Results First Posted : February 27, 2018
Last Update Posted : February 27, 2018
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.

Tracking Information
First Submitted Date  ICMJE October 24, 2013
First Posted Date  ICMJE October 30, 2013
Results First Submitted Date  ICMJE December 27, 2017
Results First Posted Date  ICMJE February 27, 2018
Last Update Posted Date February 27, 2018
Actual Study Start Date  ICMJE February 2014
Actual Primary Completion Date January 26, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 29, 2018)
Percentage of Participants Who Did Not Require a Platelet Transfusion or Any Rescue Procedure for Bleeding After Randomization Following a Scheduled Procedure [ Time Frame: 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).
Original Primary Outcome Measures  ICMJE
 (submitted: October 24, 2013)
The proportion of subjects who require platelet transfusion or rescue therapy for bleed after randomization ad up to 7 days after the elective procedure [ Time Frame: Approximately 20 months ]
To confirm that avatrombopag (60 mg avatrombopag for subjects with platelet count less than 40 x 10^9/L and 40 mg avatrombopag for subjects with platelet count from 40 to less than 50 x 10^9/L) is superior to placebo in removing the need for platelet transfusions or any rescue procedure for bleeding after randomization and up to 7 days following an elective procedure in subjects with chronic liver disease who have thrombocytopenia.
Change History Complete list of historical versions of study NCT01972529 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 29, 2018)
  • Percentage of Participants Who Achieved a Platelet Count Greater Than or Equal to 50 x 10^9/L on the Scheduled Procedure Day [ Time Frame: 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).
  • Change From Baseline in Platelet Count on the Scheduled Procedure Day [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 24, 2013)
  • Proportion of subjects who achieve a platelet counts >= 50 x109/L on Procedure day [ Time Frame: Approximately 20 months ]
    To confirm that avatrombopag is superior to placebo in achieving a platelet count of greater than or equal to 50 x 109/L on Procedure Day in the proposed target population
  • Change from baseline of platelet counts on Procedure Day [ Time Frame: Up to approximately 20 months ]
    To confirm that avatrombopag is superior to placebo in elevating platelet counts from baseline on Procedure Day in the proposed target population
  • Proportion of subjects with a WHO bleeding score >= 2 after randomization and up to 7 days after an elective procedure [ Time Frame: Approximately 20 months ]
    To evaluate whether the observed incidence of bleeding in subjects treated with avatrombopag is noninferior to placebo in those subjects expected to receive a platelet transfusion prior to their procedure
  • Safety of avatrombopag [ Time Frame: Approximately 20 months ]
    Safety assessments will consist of monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs), including platelet transfusion-related complications; routine laboratory evaluations.
Current Other Pre-specified Outcome Measures
 (submitted: January 29, 2018)
  • Percentage of Participants With a World Health Organization (WHO) Bleeding Score Greater Than or Equal to 2 After a Scheduled Procedure [ Time Frame: 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.
  • Number of Participants Experiencing an Adverse Event [ 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 ]
    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.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment of Thrombocytopenia in Patients With Chronic Liver DiseaseUndergoing an Elective Procedure
Official Title  ICMJE 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
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).
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Thrombocytopenia Associated With Liver Disease
Intervention  ICMJE
  • Drug: avatrombopag (lower baseline platelet count)
    60 mg avatrombopag (3 x 20 mg tablets)
  • Drug: placebo (lower baseline platelet count)
    60 mg placebo (3 x 20 mg matching placebo tablets)
  • Drug: avatrombopag (higher baseline platelet count)
    40 mg avatrombopag (2 x 20 mg tablets)
  • Drug: placebo (higher baseline platelet count)
    40 mg placebo (2 x 20 mg matching placebo tablets)
Study Arms  ICMJE
  • Experimental: Group A (avatrombopag, lower baseline platelet count)
    60 mg avatrombopag (3 x 20 mg tablets) once daily on Days 1 through 5
    Intervention: Drug: avatrombopag (lower baseline platelet count)
  • Placebo Comparator: Group B (placebo, lower baseline platelet count)
    placebo (3 x 20 mg matching placebo tablets) once daily on Days 1 through 5
    Intervention: Drug: placebo (lower baseline platelet count)
  • Experimental: Group C (avatrombopag, higher baseline platelet count)
    40 mg avatrombopag (2 x 20 mg tablets) once daily on Days 1 through 5
    Intervention: Drug: avatrombopag (higher baseline platelet count)
  • Placebo Comparator: Group D (placebo, higher baseline platelet count)
    placebo (2 x 20 mg matching placebo tablets) once daily on Days 1 through 5
    Intervention: Drug: placebo (higher baseline platelet count)
Publications * Terrault N, Chen YC, Izumi N, Kayali Z, Mitrut P, Tak WY, Allen LF, Hassanein T. Avatrombopag Before Procedures Reduces Need for Platelet Transfusion in Patients With Chronic Liver Disease and Thrombocytopenia. Gastroenterology. 2018 Sep;155(3):705-718. doi: 10.1053/j.gastro.2018.05.025. Epub 2018 May 17.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 18, 2017)
231
Original Estimated Enrollment  ICMJE
 (submitted: October 24, 2013)
300
Actual Study Completion Date  ICMJE February 27, 2017
Actual Primary Completion Date January 26, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Brazil,   Canada,   Chile,   China,   France,   Germany,   Hungary,   Italy,   Korea, Republic of,   Poland,   Portugal,   Spain,   Taiwan,   Thailand,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01972529
Other Study ID Numbers  ICMJE E5501-G000-310
2013-000965-34 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Eisai Inc.
Study Sponsor  ICMJE Eisai Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Eisai Inc.
Verification Date January 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP