Eltrombopag Combined With Low-dose Rituximab in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies

• ClinicalTrials.gov Identifier: NCT04915482
• Recruitment Status: Recruiting
• First Posted: June 7, 2021
• Last Update Posted: May 11, 2022
• Sponsor: Institute of Hematology & Blood Diseases Hospital
• Information provided by (Responsible Party): Zhang Lei, Institute of Hematology & Blood Diseases Hospital

Study Description

Brief Summary:

This prospective, open-label, nonrandomized, multicenter clinical trial aims at comparing the efficacy and safety of combined use of eltrombopag with low-dose rituximab vs. the best available therapy（BAT）in adult immune thrombocytopenia with autoantibodies fail (due to intolerance or resistance) to first-line treatment.

Condition or disease	Intervention/treatment	Phase
Immune Thrombocytopenia (ITP); Autoantibodies; Evan Syndrome; Connective Tissue Diseases	Drug: Combined use of eltrombopag with low-dose rituximab; Drug: The best available therapy	Phase 4

Detailed Description:

This is a prospective, open-label, nonrandomized, multicenter clinical trial aiming at comparing the efficacy and safety of combined use of eltrombopag with low-dose rituximab vs. the best available therapy（BAT）in adult immune thrombocytopenia (ITP) with autoantibodies fail (due to intolerance or resistance) to first-line treatment. The subjects include ITP secondary to connective tissue diseases (including but not limited to systemic lupus erythematosus, Sjogren's syndrome and rheumatoid arthritis), primary ITP with positive antinuclear antibody but not up to the diagnostic criteria of connective tissue diseases, primary Evans syndrome, Evans syndrome secondary to connective tissue diseases, and primary ITP with positive Coomb's test but not up to the diagnostic criteria of Evans syndrome.

Adult ITP patients with autoantibodies (18-65 years) will be nonrandomly divided into the following two treatment groups: 1. combined use of eltrombopag with low-dose rituximab. 2. the best available therapy（BAT）other than combined use of eltrombopag with rituximab.

The current treatment strategies and possible risks of combined use of eltrombopag with low-dose rituximab in the treatment of ITP with autoantibodies will be fully introduced to the patients by the researchers. Then the patients will be divided into one of the two groups according to the patients' will.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 94 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Eltrombopag Combined With Low-dose Rituximab in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies Fail to First-line Treatment: a Prospective, Open-label, Nonrandomized, Multicenter Clinical Trial
• Actual Study Start Date: June 6, 2021
• Estimated Primary Completion Date: January 31, 2024
• Estimated Study Completion Date: February 28, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Combined use of eltrombopag with low-dose rituximab; The starting dose of eltrombopag is 75mg daily. Before or within 4 weeks after the treatment, rituximab 375mg/m2 will be used once. The dosage will be adjusted according to the results of laboratory examinations and patient tolerance. If the continuous application of 75 mg once a day of eltrombopag for 6 weeks is still ineffective, discontinue the use of eltrombopag.	Drug: Combined use of eltrombopag with low-dose rituximab; The starting dose of eltrombopag is 75mg daily. Before or within 4 weeks after the treatment, rituximab 375mg/m2 will be used once. The dosage will be adjusted according to the results of laboratory examinations and patient tolerance.
Active Comparator: The best available therapy other than combined use of eltrombopag with rituximab; The best available therapy except for combined use of eltrombopag with rituximab includes but not limited to glucocorticoids, intravenous immunoglobulin, recombinant human thrombopoietin, TPO receptor agonists other than eltrombopag, rituximab monotherapy, immunosuppressants, etc., and the researchers will adjust the treatment plan at any time according to the patient's condition.	Drug: The best available therapy; The best available therapy includes but not limited to glucocorticoids, intravenous immunoglobulin, recombinant human thrombopoietin, TPO receptor agonists other than eltrombopag, rituximab monotherapy, immunosuppressants, etc.

Outcome Measures

Primary Outcome Measures :

1. Platelet response [ Time Frame: From the start of study treatment (Day 1) up to the end of week 24 ]
   At weeks 4-24, the proportion of subjects with platelet count (PLT) ≥30×10^9/L and at least 2 times the baseline value in 4 out of 6 consecutive tests (at least 1 week interval between each test).

Secondary Outcome Measures :

1. Platelet response [ Time Frame: From the start of study treatment (Day 1) up to the end of week 4, 8 and 12 ]
   Proportion of subjects who achieve response (R) within 4, 8 and 12 weeks of treatment.
2. Platelet response [ Time Frame: From the start of study treatment (Day 1) up to the end of week 4, 8 and 12 ]
   Proportion of subjects who achieve complete response (CR) within 4, 8 and 12 weeks of treatment.
3. Time to platelet response [ Time Frame: From the start of study treatment (Day 1) up to the end of week 24 ]
   Time to response is defined as time from the start of treatment to the first time of achieving a platelet count ≥ 30×10^9/ L and at least doubling of the baseline count during the whole 24 weeks.
4. Duration of platelet response [ Time Frame: From the start of study treatment (Day 1) up to the end of week 24 ]
   Total duration of time a participant with a response of R.
5. Bleeding score [ Time Frame: From the start of study treatment (Day 1) up to the end of week 24 ]
   The incidence and grade of bleeding symptoms according to the World Health Organization Bleeding Scale.
6. ITP-Patient Assessment Questionnaire [ Time Frame: From the start of study treatment (Day 1) up to the end of week 24 ]
   In all participants, ITP-Patient Assessment Questionnaire will be used to assess the health related quality of life before and after treatment.
7. Changes of disease activity index in patients with systemic lupus erythematosus [ Time Frame: From the start of study treatment (Day 1) up to the end of week 24 ]
   The proportion of subjects with improvement of disease activity index in patients with systemic lupus erythematosus according to the SLEDAI standard.
8. The improvement of symptoms [ Time Frame: From the start of study treatment (Day 1) up to the end of week 24 ]
   The proportion of subjects with improvement of symptoms including skin symptom, joint pain, dry mouth and dry eyes.
9. Improvement in immune indexes [ Time Frame: From the start of study treatment (Day 1) up to the end of week 24 ]
   The proportion of subjects with improvement immune indexes including antinuclear antibody, extractable nuclear antigens spectrum and Coomb's test.
10. Discontinuation rate of glucocorticoids [ Time Frame: From the start of study treatment (Day 1) up to the end of week 24 ]
    The proportion of subjects with discontinuation use of glucocorticoids.
11. Hemoglobin response [ Time Frame: From the start of study treatment (Day 1) up to the end of week 24 ]
    The proportion of subjects with Evans syndrome who have a hemoglobin level > 110g/L (female) or > 120g/L (male) in the absence of any recent transfusion and without ongoing hemolysis for 2 consecutive weeks (at least 1 week interval).
12. Hemoglobin response [ Time Frame: From the start of study treatment (Day 1) up to the end of week 24 ]
    The proportion of subjects with Evans syndrome who have a hemoglobin level> 100g/L with at least a 20g/L increase from the pretreatment level for 2 consecutive weeks (at least 1 week interval).
13. functional assessment of chronic illness therapy-fatigue [ Time Frame: From the start of study treatment (Day 1) up to the end of week 24 ]
    In all participants, functional assessment of chronic illness therapy-fatigue questionnaire will be used to assess the health related quality of life before and after treatment.

Other Outcome Measures:

1. Incidence of Toxicity [ Time Frame: From the start of study treatment (Day 1) up to the end of week 24 ]
   The proportion of subjects with specific pre-defined toxicity, including fever, hypotension, infection, elevated bilirubin, abnormal liver function, cataract and headache, and unpredictable toxicity.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• The patients have provided written informed consent prior to enrollment.
• 18-65 years old.
• Diagnosed as ITP secondary to connective tissue diseases (including but not limited to systemic lupus erythematosus, Sjogren's syndrome and rheumatoid arthritis), primary ITP with positive antinuclear antibody but not up to the diagnostic criteria of connective tissue diseases, primary Evans syndrome, Evans syndrome secondary to connective tissue diseases, and primary ITP with positive Coomb's test but not up to the diagnostic criteria of Evans syndrome.
• Platelet count<30 ×10^9/L at screening.
• Patients who have received at least one first-line treatment of ITP (glucocorticoid and / or intravenous immunoglobulin) in the past, failed (poor efficacy, or failure to maintain efficacy, or relapse), or had contraindications, intolerance, or refusal of first-line treatment.
• Treatment for ITP (including but not limited to glucocorticoids, recombinant human thrombopoietin (rTPO), and other TPO receptor agonists other than eltrombopag) must be completed before enrollment, or the dose must be stable or in a phase of reduction within 2 weeks before enrollment. Immunosuppressants (including but not limited to azathioprine, danazol, cyclosporine A, mycophenolate mofetil) must be finished before entering the group, or the dose must be stable or in the reduction period within 3 months before entering the group.
• Effective contraceptive measures will be taken during the clinical trial.

Exclusion Criteria:

• Thrombocytopenia secondary to thyroid disease.
• Patients with any prior history of arterial or venous thrombosis, and with any of the following risk factors: cancer, Factor V Leiden, ATIII deficiency, and antiphospholipid syndrome.
• Those who had received rituximab within 6 months or who had previously failed to respond to low-dose rituximab.
• Patients who had failed to respond to the previous use of eltrombopag (75 mg once a day for more than 4 weeks).
• Patients who have received splenectomy within one year or have splenectomy plan within one year.
• Patients with lupus encephalopathy or lupus nephritis.
• Patients with cataract.
• Patients with infectious fever (including but not limited to pulmonary infection) within 1 month or with active infection during screening.
• Existing hepatitis B virus, hepatitis C virus replication or HIV infection.
• Patients with agranulocytosis (ANC <1× 10^9/L), or moderate and severe anemia (HGB < 90g/L). For patients with Evans syndrome, patients with HGB< 60g/L will be excluded.
• Severe liver dysfunction (alanine aminotransferase or glutamic oxaloacetic transaminase > 3×ULN), or bilirubin level > 2×ULN except patients with Evans syndrome.
• Patients with severe cardiac or pulmonary dysfunction.
• Severe renal damage (creatinine clearance < 50 ml/min).
• There were surgical planners during the study.
• History of psychiatric disorder.
• Pregnant or lactating women or those planning to be pregnant during the trial.
• Patients with a history of drug/alcohol abuse (within 2 years before the study).
• Patients that have participated in other experimental researches within one month before enrollment.
• Any other circumstances that the investigator considers that the patient is not suitable to participate in the trial.

Contacts and Locations

Contacts

Contact: Rongfeng Fu, MD; +862223909009; furongfeng@ihcams.ac.cn

Contact: Lei Zhang, MD; +862223909240; zhanglei1@ihcams.ac.cn

Locations

China, Tianjin

Institute of Hematology & Blood Diseases Hospital; Recruiting

Tianjin, Tianjin, China, 300020

Contact: Rongfeng Fu, MD +862223909009 furongfeng@ihcams.ac.cn

Contact: Lei Zhang, MD +862223909240 zhanglei1@ihcams.ac.cn

Sponsors and Collaborators

Institute of Hematology & Blood Diseases Hospital

Investigators

• Principal Investigator: Lei Zhang, MD; Institute of Hematology & Blood Diseases Hospital

More Information

• Responsible Party: Zhang Lei, Professor/Vice director of Thrombosis &Hemostasis Center, Institute of Hematology & Blood Diseases Hospital
• ClinicalTrials.gov Identifier: NCT04915482
• Other Study ID Numbers: IHBDH-ITP-2020001
• First Posted: June 7, 2021
• Last Update Posted: May 11, 2022
• Last Verified: May 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Thrombocytopenia; Immune System Diseases; Purpura, Thrombocytopenic, Idiopathic; Connective Tissue Diseases; Blood Platelet Disorders; Hematologic Diseases; Purpura, Thrombocytopenic; Purpura; Blood Coagulation Disorders; Thrombotic Microangiopathies; Hemorrhagic Disorders; Autoimmune Diseases; Hemorrhage; Pathologic Processes; Skin Manifestations; Rituximab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents