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

NCT ID: NCT01976104

Last Updated: 2018-02-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 204 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-11-30
• Study Completion Date: 2017-02-21

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 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

• 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

Birmingham, Alabama, United States

Phoenix, Arizona, United States

Little Rock, Arkansas, United States

Coronado, California, United States

Loma Linda, California, United States

Denver, Colorado, United States

Miami, Florida, United States

Maywood, Illinois, United States

Indianapolis, Indiana, United States

Kansas City, Kansas, United States

New Orleans, Louisiana, United States

Baltimore, Maryland, United States

Boston, Massachusetts, United States

Detroit, Michigan, United States

Kansas City, Missouri, United States

New York, New York, United States

Statesville, North Carolina, United States

Charleston, South Carolina, United States

Houston, Texas, United States

San Antonio, Texas, United States

Charlottesville, Virginia, United States

Richmond, Virginia, United States

Seattle, Washington, United States

Ciudad Autonoma Buenos Aires, , Argentina

Córdoba, , Argentina

Rosario, , Argentina

Clayton, Victoria, Australia

Footscray, Victoria, Australia

Melbourne, Victoria, Australia

Parkville, Victoria, Australia

Edegem, , Belgium

Ghent, , Belgium

Liège, , Belgium

Aracaju, , Brazil

Botucatu, , Brazil

Porto Alegre, , Brazil

Salvador, , Brazil

Calgary, , Canada

Edmonton, , Canada

Hefei, Anhui, China

Beijing, Beijing Municipality, China

Shijiazhuang, Hebei, China

Nanjing, Jiangsu, China

Xi'an, Shaanxi, China

Xi’an, Shanxi, China

Chengdu, Sichuan, China

Hangzhou, Zheijiang, China

Brno, , Czechia

Havířov, , Czechia

Ostrava, , Czechia

Prague, , Czechia

Ústí nad Labem, , Czechia

Nice, Alpes Maritimes, France

Clichy, Hauts De Seine, France

Rennes, Ille Et Vilaine, France

Lyon, Rhone, France

Villejuif, Val De Marne, France

Mannheim, Baden-Wurttemberg, Germany

Tübingen, Baden-Wurttemberg, Germany

Frankfurt am Main, Hesse, Germany

Hanover, Lower Saxony, Germany

Bonn, North Rhine-Westphalia, Germany

Leipzig, Saxony, Germany

Kiel, Schleswig-Holstein, Germany

Hamburg, , Germany

Haifa, , Israel

Holon, , Israel

Jerusalem, , Israel

Nahariya, , Israel

Petah Tikva, , Israel

Ramat Gan, , Israel

Rehovot, , Israel

Tel Aviv, , Israel

Baggiovara, Modena, Italy

Florence, , Italy

Milan, , Italy

Pisa, , Italy

Roma, , Italy

Trento, , Italy

Sapporo, Hokkaido, Japan

Nishinomiya, Hyōgo, Japan

Morioka, Iwate, Japan

Takamatsu, Kagawa-ken, Japan

Yufu, Oita Prefecture, Japan

Okayama, Okayama-ken, Japan

Osaka, Osaka, Japan

Osaka-Sayama-shi, Osaka, Japan

Iruma, Saitama, Japan

Bunkyo-ku, Tokyo, Japan

Chiyoda City, Tokyo, Japan

Musashino, Tokyo, Japan

Setagaya-ku, Tokyo, Japan

Shinagawa-ku, Tokyo, Japan

Chiba, , Japan

Niigata, , Japan

Okayama, , Japan

Tokushima, , Japan

Wakayama, , Japan

Zapopan, Jalisco, Mexico

Monterrey, Nuevo León, Mexico

Orizaba, Veracruz, Mexico

Mérida, Yucatán, Mexico

Durango, , Mexico

Arad, , Romania

Bucharest, , Romania

Craiova, , Romania

Iași, , Romania

Sibiu, , Romania

Timișoara, , Romania

Kemerovo, , Russia

Moscow, , Russia

Saint Petersburg, , Russia

Samara, , Russia

L'Hospitalet de Llobregat, Barcelona, Spain

Cáceres, Cáceres, Spain

Barcelona, , Spain

Girona, , Spain

Madrid, , Spain

Valencia, , Spain

Zaragoza, , Spain

Countries

United States; Argentina; Australia; Belgium; Brazil; Canada; China; Czechia; France; Germany; Israel; Italy; Japan; Mexico; Romania; Russia; Spain

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

2013-000934-36

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

E5501-G000-311

Identifier Type: -

Identifier Source: org_study_id