Treatment of Thrombocytopenia in Patients With Chronic Liver Disease Undergoing an Elective Procedure
Condition: Thrombocytopenia Associated With Liver Disease
MeSH terms: Liver Diseases; Thrombocytopenia
Intervention: avatrombopag (lower baseline platelet count); placebo (lower baseline platelet count); avatrombopag (higher baseline platelet count); placebo (higher baseline platelet count)
Intervention description: 60 mg avatrombopag (3 x 20 mg tablets); 60 mg placebo (3 x 20 mg matching placebo tablets); 40 mg avatrombopag (2 x 20 mg tablets); 40 mg placebo (2 x 20 mg matching placebo tablets)
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 204.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Thrombocytopenia; Chronic Liver Disease

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).
    

Eligibility criteria:

        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 subjects

         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