Treatment of Thrombocytopenia in Patients With Chronic Liver Disease Undergoing an Elective Procedure

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Eisai Inc.
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.
ClinicalTrials.gov Identifier:
NCT01976104
First received: October 24, 2013
Last updated: June 4, 2014
Last verified: June 2014
  Purpose

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. Subjects 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 Intervention Phase
Thrombocytopenia Associated With Liver Disease
Drug: avatrombopag (lower baseline platelet count)
Drug: placebo (lower baseline platlet count)
Drug: avatrombopag (higer baseline platelet count)
Drug: placebo (higher baseline platelet count)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by Eisai Inc.:

Primary Outcome Measures:
  • The proportion of subjects who require platelet transfusion or rescue therapy for bleed after randomization and up to 7 days after the elective procedure [ Time Frame: Baseline and up to 7 days after day of procedure ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Proportion of subjects who achieve a platelet counts greater than or equal to 50 x 10^9/L on Procedure day [ Time Frame: Day of Procedure ] [ Designated as safety issue: No ]
    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: Baseline and Day of Procedure ] [ Designated as safety issue: No ]
    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 greater than or equal to 2 after randomization and up to 7 days after an elective procedure [ Time Frame: Baseline and up to 7 days after day of procedure ] [ Designated as safety issue: No ]
    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: Up to 20 months ] [ Designated as safety issue: Yes ]
    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. At selected sites, platelet function will also be measured using specified flow cytometric markers.


Estimated Enrollment: 300
Study Start Date: November 2013
Estimated Study Completion Date: August 2015
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 platlet 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 (higer 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)

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: Dental procedures; Paracentesis; Gastrointestinal endoscopy with or without plans for biopsy, colonoscopy, polypectomy, or variceal banding; Liver biopsy; Bronchoscopy with or without plans for biopsy; Ablation therapy (radiofrequency ablation or ethanol ablation) or chemoembolization for HCC; Vascular catheterization and Transjugular intrahepatic portosystemic shunt.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. Subjects greater than or equal to 18 years of age at Screening with chronic liver disease
  2. Subjects who have a mean baseline platelet count of less than 50 x 109/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 109/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. Subjects 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
  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. Adequate portal vein blood flow at Screening
  4. Hepatic encephalopathy that cannot be effectively treated
  5. Subjects with HCC with Barcelona Clinic Liver Cancer (BCLC) staging classification C or D
  6. Platelet transfusion or receipt of blood products containing platelets within 7 days of Screening. However packed red blood cells are permitted.
  7. Heparin, warfarin, nonsteroidal anti-inflammatory drugs (NSAID), aspirin, verapamil, and antiplatelet therapy with ticlopidine or glycoprotein IIb/IIIa antagonists (eg, tirofiban) within 7 days of Screening
  8. Use of erythropoietin stimulating agents within 7 days of Screening
  9. Interferon (IFN) use within 14 days of Screening
  10. Estrogen-containing hormonal contraceptive or hormone replacement therapy use within 30 days of Screening
  11. Active infection requiring systemic antibiotic therapy within 7 days of Screening. However, prophylactic use of antibiotics is permitted.
  12. Alcohol abuse, alcohol dependence syndrome, drug abuse, or drug dependence within 6 months of the study start (unless participating in a controlled rehabilitation program) or acute alcoholic hepatitis (chronic alcoholic hepatitis is allowed) within 6 months of the study start
  13. 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
  18. Subjects with a history of significant cardiovascular disease (eg, congestive heart failure New York Heart Association Grade III/IV, arrhythmia known to increase the risk of thromboembolic events [eg, atrial fibrillation], coronary artery stent placement, angioplasty, and coronary artery bypass grafting)
  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 subject must agree to use a double-barrier method as described above if she becomes sexually active during the study period or for 30 days after study drug discontinuation. All females will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrhea in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) at least 1 month before dosing.
  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 subjects
  22. Any subject who has previously received avatrombopag
  23. Hypersensitivity to avatrombopag maleate or any of its excipients
  24. Hemoglobin levels less than or equal to 8.0 or greater than or equal to 16.0 g/dL at Screening
  25. White blood cell count less than or equal to 1.5 x 10^9/L or greater than or equal to 15.0 x 10^9/L at Screening
  26. Serum sodium level less than or equal to 130 mEq/L at Screening
  27. Current malignancy including solid tumors and hematologic malignancies (except HCC)
  28. Any history of or concomitant medical condition that, in the opinion of the investigator(s), would compromise the subject's ability to safely complete the study
  29. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days of Screening
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01976104

Contacts
Contact: Eisai Medical Services 1-888-422-4743

  Show 69 Study Locations
Sponsors and Collaborators
Eisai Inc.
  More Information

No publications provided

Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT01976104     History of Changes
Other Study ID Numbers: E5501-G000-311, 2013-000934-36
Study First Received: October 24, 2013
Last Updated: June 4, 2014
Health Authority: European Union: European Medicines Agency
United States: Food and Drug Administration

Keywords provided by Eisai Inc.:
Thrombocytopenia
Chronic Liver Disease

Additional relevant MeSH terms:
Liver Diseases
Thrombocytopenia
Digestive System Diseases
Blood Platelet Disorders
Hematologic Diseases

ClinicalTrials.gov processed this record on October 01, 2014