to Evaluate the Efficacy and Safety of Eltrombopag for Thrombocytopenia With Chronic HBV Infection

• ClinicalTrials.gov Identifier: NCT03664518
• Recruitment Status: Completed
• First Posted: September 10, 2018
• Last Update Posted: January 26, 2023
• Sponsor: Institute of Hematology & Blood Diseases Hospital
• Collaborators: Novartis; Qilu Hospital of Shandong University; The Second Affiliated Hospital of Kunming Medical University; Tianjin First Central Hospital; Tianjin Medical University Second Hospital; Henan Cancer Hospital; The Second Hospital of Hebei Medical University; North China University of Technology Affiliated Hospital; The Affiliated Hospital of Qingdao University; The First Affiliated Hospital of University of Science and Technology of China; The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School; Second Affiliated Hospital of Guangzhou Medical University
• Information provided by (Responsible Party): Zhang Lei, MD, Institute of Hematology & Blood Diseases Hospital

Study Description

Brief Summary:

Primary Objective: To evaluate the efficacy of 6-week Eltrombopag to treat thrombocytopenia associated with chronic hepatitis B virus infection. Secondary Objective: To evaluate the efficacy and safety of 6-week and 22-week Eltrombopag to treat thrombocytopenia associated with chronic hepatitis B virus infection.

Condition or disease	Intervention/treatment	Phase
Thrombocytopenia Purpura; Chronic HBV Infection	Drug: Eltrombopag	Phase 2

Detailed Description:

This is a single-arm phase II study to evaluate the efficacy and safety of Eltrombopag to treat thrombocytopenia associated with chronic hepatitis B virus infection.

This study includes two stages. In Stage 1 (Week 1 to Week 6), the short-term efficacy, safety and tolerability of Eltrombopag is evaluated. At the end of Stage 1, the subjects who can benefit from Eltrombopag treatment (platelet count ≥30×109/L at least once and a 2-fold increase from baseline platelet count without rescue therapy, with no bleeding) can enter a 16-week prolonged stage (Stage 2) to evaluate longer-term efficacy and safety.

The starting dose of Eltrombopag is 25 mg once daily, and the dose may be increased by 25 mg once daily according to protocol if the desired platelet response (>50×109/L) is not achieved. The daily dose should not exceed 75 mg.

In Stage 1, weekly visits are required during the first 6 weeks of the study. In Stage 2, platelet counts will be obtained weekly during dose adjustment and every 4 weeks following establishment of a stable dose of Eltrombopag (stable dose is defined as the dose which remains unchanged for at least 2 weeks).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 48 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter Single-arm Study to Evaluate the Efficacy and Safety of Eltrombopag for Thrombocytopenia in Chinese Patients With Chronic HBV Infection
• Actual Study Start Date: December 4, 2018
• Actual Primary Completion Date: June 30, 2022
• Actual Study Completion Date: September 30, 2022

Arms and Interventions

Arm

Intervention/treatment

Experimental: Eltrombopag; 58 enrolled patients are picked up to take eltrombopag at the indicated dose.

Drug: Eltrombopag; subjects will initiate treatment with 25 mg eltrombopag. Platelet counts is obtained weekly and dose adjustment should be done according to platelet counts. and maximum dose should not exceed 75 mg daily. Subjects whose platelet count between 50~150×109/L，the eltrombopag dose Maintain. platelet count between 150~250×109/L, need to reduce the dose of eltrombopag to the next lower dose or lower frequency. Subjects whose platelet count exceeds 250×109/L at any point during the treatment period, must have eltrombopag interrupted and increase the frequency of platelet monitoring to twice weekly, until platelet counts fall below 100×109/L.

Outcome Measures

Primary Outcome Measures :

1. Proportion of subjects with a platelet count ≥ 50×109/L at Day 43 [ Time Frame: 6 weeks ]
   The proportion of subjects with a platelet count ≥ 50×109/L at Day 43 after the first 6 weeks of Eltrombopag treatment (Stage 1)

Secondary Outcome Measures :

1. Response rate of treatment [ Time Frame: 22 weeks ]
   Response rate including: a) the proportion of subjects achieving platelet counts ≥ 50×109/L at least once during the first 6 weeks (stage 1); b) the proportion of subjects whose platelet counts ≥ 30×109/L and at least two times of baseline platelet count at least once during the treatment.
2. Bleeding in two stages [ Time Frame: 22 weeks ]
   according to the WHO bleeding grades to estimate the incidence and severity of bleeding symptoms during the treatment.
3. The duration time with Platelet count ≥ 50×109/L [ Time Frame: 22 weeks ]
   Total duration of time a subject had a platelet count ≥ 50×109/L during treatment.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Signed written informed consent.
• Subject is ≥18 years old.
• Diagnosis of HBV-infection duration for at least 6 months prior to the study and have a platelet count of <30 ×109/L on Day 1 (or within 48 hours prior to dosing on Day 1).
• Complete blood count results: white blood cells, absolute neutrophils count and hemoglobin are within the laboratory normal range, but abnormalities caused by HBV infection can be accepted.
• Subject is practicing an acceptable method of contraception. Women of childbearing potential must have a negative serum pregnancy test in the whole study.

Exclusion Criteria:

• Liver cirrhosis (LC) defined as any of the following:

  1. Any symptom or sign typical of hepatic decompensation: including but not limited to ascites, splenomegaly, dilation of periumbilical collateral veins, hepatic encephalopathy
  2. Child-Pugh class B to C Biopsies are not required either for confirmation or for exclusion of LC, considering the high bleeding risk in these patients.
• Positive serology for HIV, hepatitis C virus (HCV), and/or hepatitis D virus (HDV).
• Pregnancy or lactation period.
• History of alcohol/drug abuse or dependence within 12 months of the study.
• History of thrombosis.
• The serum chemistry results exceed the upper laboratory normal range by more than 20%; except AST, ALT, GGT, ALP of CTCAE grade 1.
• Bone marrow examination conducted within 4 weeks prior to first dose reported an abnormal result, which in the opinion of the investigator makes the subject unsuitable for participation in the study.
• Pre-existing cardiac disease, including congestive heart failure of New York Heart Association [NYHA] Grade III/IV, arrhythmia requiring treatment or myocardial infarction within the last 6 months. No arrhythmia known to increase the risk of thrombotic events (e.g. atrial fibrillation), or patients with a QT >450msec or QTc > 480 for patients with a Bundle Branch Block.
• Subject has consumed aspirin, aspirin-containing compounds, salicylates, anticoagulants, quinine or non-steroidal anti-inflammatories (NSAIDs) for >3 consecutive days within 2 weeks prior to the study start and until the end of the study.
• Non-compliant patient
• Reluctance to take effective contraceptive measures during the trial
• History of solid organ or bone marrow transplant.

Contacts and Locations

Locations

China, Tianjin

Ethics Committee of Blood disease hospital, Chinese Academy of Medical Sciences

Tianjin, Tianjin, China, 300020

Sponsors and Collaborators

Institute of Hematology & Blood Diseases Hospital

Novartis

Qilu Hospital of Shandong University

The Second Affiliated Hospital of Kunming Medical University

Tianjin First Central Hospital

Tianjin Medical University Second Hospital

Henan Cancer Hospital

The Second Hospital of Hebei Medical University

North China University of Technology Affiliated Hospital

The Affiliated Hospital of Qingdao University

The First Affiliated Hospital of University of Science and Technology of China

The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Second Affiliated Hospital of Guangzhou Medical University

Investigators

• Principal Investigator: lei zhang, MD; Chinese Academy of Medical Science and Blood Disease Hospital

More Information

Publications of Results:

Yang R, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Hou M. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. Br J Haematol. 2017 Jan;176(1):101-110. doi: 10.1111/bjh.14380. Epub 2016 Oct 13.

Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani H, Mayer B, Stone NL, Arning M, Provan D, Jenkins JM. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007 Nov 29;357(22):2237-47. doi: 10.1056/NEJMoa073275.

Giannini EG, Afdhal NH. Eltrombopag in patients with chronic liver disease. Expert Opin Pharmacother. 2013 Apr;14(5):669-78. doi: 10.1517/14656566.2013.775249. Epub 2013 Mar 4.

Other Publications:

Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 2012 Mar 9;30(12):2212-9. doi: 10.1016/j.vaccine.2011.12.116. Epub 2012 Jan 24.

Zhang Y, Zhang H, Elizabeth A, Liu XQ. Epidemiology of hepatitis B and associated liver diseases in china. Chin Med Sci J. 2013 Jan;27(4):243-8. doi: 10.1016/s1001-9294(13)60009-7.

Toghill PJ, Green S, Ferguson F. Platelet dynamics in chronic liver disease with special reference to the role of the spleen. J Clin Pathol. 1977 Apr;30(4):367-71. doi: 10.1136/jcp.30.4.367.

Aref S, Mabed M, Selim T, Goda T, Khafagy N. Thrombopoietin (TPO) levels in hepatic patients with thrombocytopenia. Hematology. 2004 Oct-Dec;9(5-6):351-6. doi: 10.1080/10245330400010620.

Afdhal N, McHutchison J, Brown R, Jacobson I, Manns M, Poordad F, Weksler B, Esteban R. Thrombocytopenia associated with chronic liver disease. J Hepatol. 2008 Jun;48(6):1000-7. doi: 10.1016/j.jhep.2008.03.009. Epub 2008 Mar 31.

Bussel JB, Marks KM. How effective is eltrombopag for the treatment of thrombocytopenia in patients with HCV infection? Nat Clin Pract Gastroenterol Hepatol. 2008 Aug;5(8):424-5. doi: 10.1038/ncpgasthep1185. Epub 2008 Jul 8. No abstract available.

• Responsible Party: Zhang Lei, MD, vice Director of Thrombosis and Hemostasis Center, Institute of Hematology & Blood Diseases Hospital
• ClinicalTrials.gov Identifier: NCT03664518
• Other Study ID Numbers: IHBDH-IIT2018006
• First Posted: September 10, 2018
• Last Update Posted: January 26, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Researchers qualified can request the dataset, including de-identified individual subject data. Data may be requested from PI from 12 months 36 months after study completion.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: From 12 months 36 months after study completion.
• Access Criteria: Upon request to PI.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Infections; Communicable Diseases; Thrombocytopenia; Purpura; Purpura, Thrombocytopenic; Disease Attributes; Pathologic Processes; Blood Platelet Disorders; Hematologic Diseases; Blood Coagulation Disorders; Hemorrhage; Skin Manifestations; Thrombotic Microangiopathies; Immune System Diseases