Clinical trial NCT01976104: Treatment of Thrombocytopenia in Patients With Chronic Liver Disease Undergoing an Elective Procedure
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Thrombocytopenia Associated With Liver Disease
Keywords: Thrombocytopenia
Chronic Liver Disease
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2013-11-05
Enrollment: 204
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Percentage of Participants Who Did Not Require a Platelet Transfusion After Randomization and up to 7 Days Following a Scheduled Procedure
timeFrame: Randomization (Visit 2), up to 7 Days following a scheduled procedure
Secondary outcomes:
measure: Percentage of Participants Who Achieved a Platelet Count Greater Than or Equal to 50 x 10^9/L on Scheduled Procedure Day
timeFrame: Day 10 to Day 13 (Visit 4)
measure: Change From Baseline in Platelet Counts on Scheduled Procedure Day
timeFrame: Baseline (Visit 2) to Procedure Day 10 to Day 13 (Visit 4)
Other outcomes:
measure: Percentage of Participants With a World Health Organization (WHO) Bleeding Score Greater Than or Equal to 2 After Randomization and up to 7 Days After an Scheduled Procedure
timeFrame: Baseline (Visit 2) up to 7 days post scheduled procedure
measure: Number of Participants Experiencing an Adverse Event
timeFrame: From date of first dose of study drug up to 30 days after the last dose of study drug, up to approximately 3 years and 2 months
Locations:
city: Birmingham
country: United States
state: Alabama
city: Phoenix
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state: Arizona
city: Little Rock
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state: Arkansas
city: Coronado
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state: California
city: Loma Linda
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state: California
city: Denver
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state: Colorado
city: Miami
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state: Illinois
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state: Indiana
city: Kansas City
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state: Kansas
city: New Orleans
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state: Louisiana
city: Baltimore
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state: Maryland
city: Boston
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state: Massachusetts
city: Detroit
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state: Michigan
city: Kansas City
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state: Missouri
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state: New York
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state: North Carolina
city: Charleston
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state: South Carolina
city: Houston
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state: Texas
city: San Antonio
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state: Texas
city: Charlottesville
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state: Virginia
city: Richmond
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state: Virginia
city: Seattle
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state: Washington
city: Ciudad Autonoma Buenos Aires
country: Argentina
city: Cordoba
country: Argentina
city: Rosario
country: Argentina
city: Clayton
country: Australia
state: Victoria
city: Footscray
country: Australia
state: Victoria
city: Melbourne
country: Australia
state: Victoria
city: Parkville
country: Australia
state: Victoria
city: Edegem
country: Belgium
city: Gent
country: Belgium
city: Liege
country: Belgium
city: Aracaju
country: Brazil
city: Botucatu
country: Brazil
city: Porto Alegre
country: Brazil
city: Salvador
country: Brazil
city: Calgary
country: Canada
city: Edmonton
country: Canada
city: Hefei
country: China
state: Anhui
city: Beijing
country: China
state: Beijing
city: Shijiazhuang
country: China
state: Hebei
city: Nanjing
country: China
state: Jiangsu
city: Xi'an
country: China
state: Shaanxi
city: Xi'an
country: China
state: Shanxi
city: Chengdu
country: China
state: Sichuan
city: Hangzhou
country: China
state: Zheijiang
city: Brno
country: Czechia
city: Havirov
country: Czechia
city: Ostrava
country: Czechia
city: Praha 2
country: Czechia
city: Praha 4
country: Czechia
city: Usti nad Labem
country: Czechia
city: Nice Cedex 3
country: France
state: Alpes Maritimes
city: Clichy cedex
country: France
state: Hauts De Seine
city: Rennes cedex 09
country: France
state: Ille Et Vilaine
city: Lyon Cedex 04
country: France
state: Rhone
city: Villejuif
country: France
state: Val De Marne
city: Mannheim
country: Germany
state: Baden Wuerttemberg
city: Tuebingen
country: Germany
state: Baden Wuerttemberg
city: Frankfurt
country: Germany
state: Hessen
city: Hannover
country: Germany
state: Niedersachsen
city: Bonn
country: Germany
state: Nordrhein Westfalen
city: Leipzig
country: Germany
state: Sachsen
city: Kiel
country: Germany
state: Schleswig Holstein
city: Hamburg
country: Germany
city: Haifa
country: Israel
city: Holon
country: Israel
city: Jerusalem
country: Israel
city: Nahariya
country: Israel
city: Petach Tikva
country: Israel
city: Ramat-Gan
country: Israel
city: Rechovot
country: Israel
city: Tel Aviv
country: Israel
city: Baggiovara
country: Italy
state: Modena
city: Firenze
country: Italy
city: Milano
country: Italy
city: Pisa
country: Italy
city: Roma
country: Italy
city: Trento
country: Italy
city: Sapporo-shi
country: Japan
state: Hokkaido
city: Nishinomiya
country: Japan
state: Hyogo
city: Morioka
country: Japan
state: Iwate
city: Takamatsu
country: Japan
state: Kagawa
city: Yufu
country: Japan
state: Oita
city: Okayama-shi
country: Japan
state: Okayama
city: Osaka-Sayama-shi
country: Japan
state: Osaka
city: Osaka-shi
country: Japan
state: Osaka
city: Iruma
country: Japan
state: Saitama
city: Bunkyo-ku
country: Japan
state: Tokyo
city: Chiyoda
country: Japan
state: Tokyo
city: Musashino
country: Japan
state: Tokyo
city: Setagaya-ku
country: Japan
state: Tokyo
city: Shinagawa-ku
country: Japan
state: Tokyo
city: Chiba
country: Japan
city: Niigata
country: Japan
city: Okayama
country: Japan
city: Tokushima
country: Japan
city: Wakayama
country: Japan
city: Zapopan
country: Mexico
state: Jalisco
city: Monterrey
country: Mexico
state: Nuevo León
city: Orizaba
country: Mexico
state: Veracruz
city: Merida
country: Mexico
state: Yucatán
city: Durango
country: Mexico
city: Arad
country: Romania
city: Bucharest
country: Romania
city: Bucuresti
country: Romania
city: Craiova
country: Romania
city: Iasi
country: Romania
city: Sibiu
country: Romania
city: Timisoara
country: Romania
city: Kemerovo
country: Russian Federation
city: Moscow
country: Russian Federation
city: Saint Petersburg
country: Russian Federation
city: Samara
country: Russian Federation
city: Hospitalet de Llobregat
country: Spain
state: Barcelona
city: Caceres
country: Spain
state: Cáceres
city: Barcelona
country: Spain
city: Girona
country: Spain
city: Madrid
country: Spain
city: Valencia
country: Spain
city: Zaragoza
country: Spain
Study officials:
References:
citation: Poordad F, Terrault NA, Alkhouri N, Tian W, Allen LF, Rabinovitz M. Avatrombopag, an Alternate Treatment Option to Reduce Platelet Transfusions in Patients with Thrombocytopenia and Chronic Liver Disease-Integrated Analyses of 2 Phase 3 Studies. Int J Hepatol. 2020 Jan 25;2020:5421632. doi: 10.1155/2020/5421632. eCollection 2020.
citation: 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.