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

NCT ID: NCT01972529

Last Updated: 2018-02-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 231 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-02-28
• Study Completion Date: 2017-02-27

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.

Conditions

Thrombocytopenia Associated With Liver Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Group A (avatrombopag, lower baseline platelet count)

60 mg avatrombopag (3 x 20 mg tablets) once daily on Days 1 through 5

Group Type: EXPERIMENTAL

avatrombopag (lower baseline platelet count)

Intervention Type: DRUG

60 mg avatrombopag (3 x 20 mg tablets)

Group B (placebo, lower baseline platelet count)

placebo (3 x 20 mg matching placebo tablets) once daily on Days 1 through 5

Group Type: PLACEBO_COMPARATOR

placebo (lower baseline platelet count)

Intervention Type: DRUG

60 mg placebo (3 x 20 mg matching placebo tablets)

Group C (avatrombopag, higher baseline platelet count)

40 mg avatrombopag (2 x 20 mg tablets) once daily on Days 1 through 5

Group Type: EXPERIMENTAL

avatrombopag (higher baseline platelet count)

Intervention Type: DRUG

40 mg avatrombopag (2 x 20 mg tablets)

Group D (placebo, higher baseline platelet count)

placebo (2 x 20 mg matching placebo tablets) once daily on Days 1 through 5

Group Type: PLACEBO_COMPARATOR

placebo (higher baseline platelet count)

Intervention Type: DRUG

40 mg placebo (2 x 20 mg matching placebo tablets)

Interventions

avatrombopag (lower baseline platelet count)

60 mg avatrombopag (3 x 20 mg tablets)

Intervention Type: DRUG

placebo (lower baseline platelet count)

60 mg placebo (3 x 20 mg matching placebo tablets)

Intervention Type: DRUG

avatrombopag (higher baseline platelet count)

40 mg avatrombopag (2 x 20 mg tablets)

Intervention Type: DRUG

placebo (higher baseline platelet count)

40 mg placebo (2 x 20 mg matching placebo tablets)

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eisai Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Lancaster, California, United States

Long Beach, California, United States

Los Angeles, California, United States

Sacramento, California, United States

San Bernardino, California, United States

San Francisco, California, United States

Jacksonville, Florida, United States

Palmetto Bay, Florida, United States

Tampa, Florida, United States

New Orleans, Louisiana, United States

Rochester, Michigan, United States

Minneapolis, Minnesota, United States

Jackson, Mississippi, United States

New York, New York, United States

The Bronx, New York, United States

Philadelphia, Pennsylvania, United States

Pittsburgh, Pennsylvania, United States

Dallas, Texas, United States

Harlingen, Texas, United States

Houston, Texas, United States

San Antonio, Texas, United States

Pilar, Buenos Aires, Argentina

Ciudad Autonoma Buenos Aires, , Argentina

Mendoza, , Argentina

Camperdown, New South Wales, Australia

Adelaide, South Australia, Australia

Bedford Park, South Australia, Australia

Linz, , Austria

Vienna, , Austria

Brussels, , Belgium

Leuven, , Belgium

Porto Alegre, Rio Grande do Sul, Brazil

São José do Rio Preto, São Paulo, Brazil

São Paulo, , Brazil

London, Ontario, Canada

Toronto, Ontario, Canada

La Serena, , Chile

Santiago, , Chile

Changsha, Hu'nan, China

Nanjing, Jiangsu, China

Shanghai, Shanghai Municipality, China

Beijing, , China

Strasbourg, Bas Rhin, France

Grenoble, Isere, France

Reims, Marne, France

Clermont-Ferrand, Puy De Dome, France

Amiens, Somme, France

Vandœuvre-lès-Nancy, , France

Freiburg im Breisgau, Baden-Wurttemberg, Germany

Cologne, North Rhine-Westphalia, Germany

Herne, North Rhine-Westphalia, Germany

Kiel, Schleswig-Holstein, Germany

Hamburg, , Germany

Békéscsaba, , Hungary

Budapest, , Hungary

Dunaújváros, , Hungary

Gyula, , Hungary

Kaposvár, , Hungary

Kecskemét, , Hungary

Szombathely, , Hungary

Zalaegerszeg, , Hungary

San Giovanni Rotondo, Foggia, Italy

Bari, , Italy

Bologna, , Italy

Genova, , Italy

Milan, , Italy

Modena, , Italy

Palermo, , Italy

Udine, , Italy

Katowice, , Poland

Lodz, , Poland

Mysłowice, , Poland

Szczecin, , Poland

Wroclaw, , Poland

Coimbra, , Portugal

Lisbon, , Portugal

Porto, , Portugal

Viana do Castelo, , Portugal

Vila Real, , Portugal

Viseu, , Portugal

Chuncheon, Gangwon-do, South Korea

Guri-si, Gyeonggi-do, South Korea

Seongnam-si, Gyeonggi-do, South Korea

Suwon, Gyeonggi-do, South Korea

Yangsan, Gyeongsangnam-do, South Korea

Hwasun, Jeollanam-do, South Korea

Busan, , South Korea

Daegu, , South Korea

Incheon, , South Korea

Seoul, , South Korea

Barcelona, , Spain

Pontevedra, , Spain

Seville, , Spain

Valencia, , Spain

Valladolid, , Spain

Kaohsiung City, , Taiwan

Taichung, , Taiwan

Tainan City, , Taiwan

Taipei, , Taiwan

Taoyuan, , Taiwan

Bangkoknoi, Bangkok, Thailand

Ratchathewi, Bangkok, Thailand

Khlong Luang, Changwat Pathum Thani, Thailand

Mueang Nonthaburi, Chiang Mai, Thailand

Truro, Cornwall, United Kingdom

London, Greater London, United Kingdom

Manchester, Greater Manchester, United Kingdom

Wolverhampton, West Midlands, United Kingdom

Leeds, West Yorkshire, United Kingdom

Countries

United States; Argentina; Australia; Austria; Belgium; Brazil; Canada; Chile; China; France; Germany; Hungary; Italy; Poland; Portugal; South Korea; Spain; Taiwan; Thailand; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 32047671 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29778606 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2013-000965-34

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

E5501-G000-310

Identifier Type: -

Identifier Source: org_study_id