Clinical trial NCT01972529: Treatment of Thrombocytopenia in Patients With Chronic Liver DiseaseUndergoing 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: 2013-10-30
Enrollment: 231
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 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

Primary outcomes:
measure: Percentage of Participants Who Did Not Require a Platelet Transfusion or Any Rescue Procedure for Bleeding After Randomization Following a Scheduled Procedure
timeFrame: Baseline (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 the Scheduled Procedure Day
timeFrame: Day 10 to Day 13 (Visit 4)
measure: Change From Baseline in Platelet Count on the 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 a 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
Locations:
city: Lancaster
country: United States
state: California
city: Long Beach
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Sacramento
country: United States
state: California
city: San Bernardino
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Jacksonville
country: United States
state: Florida
city: Palmetto Bay
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: New Orleans
country: United States
state: Louisiana
city: Rochester
country: United States
state: Michigan
city: Minneapolis
country: United States
state: Minnesota
city: Jackson
country: United States
state: Mississippi
city: Bronx
country: United States
state: New York
city: New York
country: United States
state: New York
city: Philadelphia
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Dallas
country: United States
state: Texas
city: Harlingen
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Pilar
country: Argentina
state: Buenos Aires
city: Ciudad Autonoma Buenos Aires
country: Argentina
city: Mendoza
country: Argentina
city: Camperdown
country: Australia
state: New South Wales
city: Adelaide
country: Australia
state: South Australia
city: Bedford Park
country: Australia
state: South Australia
city: Linz
country: Austria
city: Vienna
country: Austria
city: Wien
country: Austria
city: Bruxelles
country: Belgium
city: Leuven
country: Belgium
city: Porto Alegre
country: Brazil
state: Rio Grande Do Sul
city: Sao Jose do Rio Preto
country: Brazil
state: Sao Paulo
city: Sao Paulo
country: Brazil
city: London
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: La Serena
country: Chile
city: Santiago
country: Chile
city: Changsha
country: China
state: Hunan
city: Nanjing
country: China
state: Jiangsu
city: Shanghai
country: China
state: Shanghai
city: Beijing
country: China
city: Strasbourg
country: France
state: Bas Rhin
city: Grenoble cedex 9
country: France
state: Isere
city: Reims
country: France
state: Marne
city: Clermont Ferrand cedex 1
country: France
state: Puy De Dome
city: Amiens cedex 1
country: France
state: Somme
city: Vandoeuvre les Nancy
country: France
city: Freiburg
country: Germany
state: Baden Wuerttemberg
city: Herne
country: Germany
state: Nordrhein Westfalen
city: Koeln
country: Germany
state: Nordrhein Westfalen
city: Kiel
country: Germany
state: Schleswig Holstein
city: Hamburg
country: Germany
city: Bekescsaba
country: Hungary
city: Budapest
country: Hungary
city: Dunaujvaros
country: Hungary
city: Gyula
country: Hungary
city: Kaposvar
country: Hungary
city: Kecskemet
country: Hungary
city: Szombathely
country: Hungary
city: Zalaegerszeg
country: Hungary
city: San Giovanni Rotondo
country: Italy
state: Foggia
city: Bari
country: Italy
city: Bologna
country: Italy
city: Genova
country: Italy
city: Milano
country: Italy
city: Modena
country: Italy
city: Palermo
country: Italy
city: Udine
country: Italy
city: Chuncheon
country: Korea, Republic of
state: Gangwon-do
city: Guri-si
country: Korea, Republic of
state: Gyeonggi-do
city: Seongnam-Si
country: Korea, Republic of
state: Gyeonggi-do
city: Suwon
country: Korea, Republic of
state: Gyeonggi-do
city: Yangsan
country: Korea, Republic of
state: Gyeongnam
city: Hwasun
country: Korea, Republic of
state: Jeollanam-do
city: Busan
country: Korea, Republic of
city: Daegu
country: Korea, Republic of
city: Incheon
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Katowice
country: Poland
city: Lodz
country: Poland
city: Myslowice
country: Poland
city: Szczecin
country: Poland
city: Wroclaw
country: Poland
city: Coimbra
country: Portugal
city: Lisboa
country: Portugal
city: Porto
country: Portugal
city: Viana do Castelo
country: Portugal
city: Vila Real
country: Portugal
city: Viseu
country: Portugal
city: Barcelona
country: Spain
city: Pontevedra
country: Spain
city: Sevilla
country: Spain
city: Valencia
country: Spain
city: Valladolid
country: Spain
city: Kaohsiung
country: Taiwan
city: Taichung
country: Taiwan
city: Tainan
country: Taiwan
city: Taipei
country: Taiwan
city: Taoyuan City
country: Taiwan
city: Bangkoknoi
country: Thailand
state: Bangkok
city: Ratchathewi
country: Thailand
state: Bangkok
city: Mueang Nonthaburi
country: Thailand
state: Chiang Mai
city: Khlong Luang
country: Thailand
state: Pathumthani
city: Truro
country: United Kingdom
state: Cornwall
city: London
country: United Kingdom
state: Greater London
city: Manchester
country: United Kingdom
state: Greater Manchester
city: Wolverhampton
country: United Kingdom
state: West Midlands
city: Leeds
country: United Kingdom
state: West Yorkshire
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.