The Efficacy and Safety of HCQ Plus TPO-RA in ANA Positive ITP

The Efficacy and Safety of Hydroxychloroquine Plus TPO-RA in Antinuclear Antibody-positive Patients With Primary Immune Thrombocytopenia-- The Multicenter, Randomized, Open-labled Clinical Trial

The goal of this clinical trial is to learn if hydroxychloroquine (HCQ) plus thrombopoietin receptor agonists (TPO-RA) works to treat primary immune thrombocytopenia with positive anti-nuclear antibodies in adults. It will also learn about the safety of HCQ plus TPO-RA. The main questions it aims to answer are:

Does HCQ plus TPO-RA raise the response rate in participants, compared to TPO-RA alone? Does HCQ plus TPO-RA prolong the response duration in participants, compared to Pred alone? Does HCQ plus TPO-RA decrease the dose of TPO-RA to maintain response in participants, compared to TPO-RA alone? What medical problems do participants have when taking HCQ plus TPO-RA? Researchers will compare HCQ plus TPO-RA with TPO-RA alone to see if HCQ plus TPO-RA works better to treat primary immune thrombocytopenia with positive anti-nuclear antibodies.

Participants will:

Take TPO-RA every day for no more than 24 weeks, adjust the dose of TPO-RA according to the platelet level, with or without HCQ twice a day for 1 year; Visit the clinic once every 1 weeks for the first 8 weeks, and once every 2-4 weeks in the following 10 months for checkups and tests; Keep a diary of their symptoms

Study Overview

• Status: Recruiting
• Conditions: Immune Thrombocytopenia With Positive ANA Antibodies
• Intervention / Treatment: Drug: Hydroxychloroquine Oral Tablet; Drug: Eltrombopag

Detailed Description

Primary immune thrombocytopenia (Primary immune thrombocytopenia, ITP) is an acquired autoimmune hemorrhagic disease characterized by a decreased peripheral platelet count and an increased risk of bleeding. It has been reported that 33.3% -39.2% of ITP patients have positive antinuclear antibodies (ANA) in the course of the disease.In the meantime, they do not meet the diagnostic criteria for rheumatic diseases such as lupus erythematosus(SLE). ITP patients with positive ANA are prone to relapse and chronicity. Therefore, it is necessary to explore new clinical treatments to attain long-term remission in these patients.

Hydroxychloroquine (HCQ) has immune modulating role on a variety of immune cells.A clinical trial enrolled immune thrombocytopenia secondary to SLE, and ITP with positive anti-nuclear antibodiy (ANA) were treated with HCQ combined with glucocorticoids. The results showed an overall response rate of 60% (24 / 40), including 18 continuous complete response (CR) and 6 continuous response (R), and some patients had continued elevated platelet counts 3 months after treatment initiation. The above studies illustrate that HCQ contributes to the treatment of chronic ITP, especially as a long-term therapeutic agent with low economic burden and good tolerance. In patients who do not response to HCQ plus corticosteroids, TPO-RA, a second line treatment, will be recommended. By now, no study has assess the efficacy and safety of HCQ plus TPO-RA in these patients. In the current study, the question will be answered.

• Study Type: Interventional
• Enrollment (Estimated): 126
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lili Ji; Phone Number: 86-021-64041990; Email: ji.lili@zs-hospital.sh.cn

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Shanghai Zhongshan Hospital
      • Contact: Lili Ji; Phone Number: 086-021-64041990; Email: ji.lili@zs-hospital.sh.cn
      • Principal Investigator: Yunfeng Cheng
    • Shanghai, Shanghai, China, 200094
      • Recruiting
      • Wusong Hospital, Zhongshan Hospital, Fudan University
      • Contact: Hongjuan Lu; Phone Number: 13564618950; Email: 13564618950@163.com
    • Shanghai, Shanghai, China, 201508
      • Recruiting
      • Shanghai Jinshan Hospital
      • Contact: Yunfeng Cheng; Phone Number: 15921398238; Email: yfcheng@fudan.edn.cn
    • Shanghai, Shanghai, China, 201700
      • Recruiting
      • Qingpu Branch of Zhongshan Hospital, Fudan University
      • Contact: Fanli Hua; Phone Number: 18116017032; Email: hua_fanli@fudan.edu.cn
• Hong Kong
  • Hong Kong, Hong Kong, 999077
    • Recruiting
    • Health and Humanity Research Centre, Hongkong, China.
    • Contact: Gregory Cheng; Phone Number: 852-60269018; Email: gregorycheng@um.edu.mo
• Macau
  • Macau, Macau, 999078
    • Recruiting
    • Dr. Stanley Ho Medical Foundation
    • Contact: Gregory Cheng; Phone Number: 852-60269018; Email: gregorycheng@um.edu.mo
  • Macau, Macau, 999078
    • Recruiting
    • University Hospital, Macau University of Science and Technology.
    • Contact: Gregory Cheng; Phone Number: 852-60269018; Email: gregorycheng@um.edu.mo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age is above 15 years old.
2. Before randomization, the clinical diagnosis is primary immune thrombocytopenia. The platelet count is less than 30×10^9 / L within 1 week before enrollment, or platelet count is less than 50×10^9 / L with bleeding symptoms within 1 week before enrollment.
3. The antinuclear antibody is positive.
4. Other autoantibodies (mainly including dsDNA antibodies, SSA, SSB, RNP, β 2-GP, ACA, ANCA) are negative.
5. Participants who had received at least two HD-DXM 40 mg/d ×4 d, failed or relapsed, or received standard dose prednisone (1-2 mg/kg/d) for 4 weeks, the platelet count remained <30×10 9 / L, or the platelet count normalized but decreased with prednisone tappering off, or prednisone 30mg to maintain the platelet number.
6. Prothrombin time does not exceed ± 3s of the normal value ranget, activated partial thrombin time is not outside normal range ± 10s; no history of coagulopathy except ITP.

(6)Understand the study procedures and sign the written informed consent form.

Exclusion Criteria:

1. Secondary thrombocytopenia caused by myelodysplastic syndrome, immune diseases such as systemic lupus erythematosus, early aplastic anemia, atypical reanemia, antiphospholipid syndrome, thrombotic thrombocytopenic purpura and various other causes.
2. The participant has experienced any arterial or venous thrombosis (stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis or pulmonary embolism), or clinical symptoms and medical history indicate thrombophilia.
3. Congestive heart disease, including New York Heart Association (NHYA) Grade III / IV, occurred within 3 months prior to screening, arrhythmia requiring medication or myocardial infarction, or arrhythmia known to increase the risk of thrombotic events (such as atrial fibrillation), or corrected QT interval (QTc) is longer than 450 ms, or QTc> 480 ms in paricipants with bundle branch block.
4. A medical history of parenchymal organ transplantation or allogeneic bone marrow transplantation.
5. Having received any medication affecting platelet function ( Including but not limited to aspirin, aspirin-containing complexes, clopidogrel, salicylates, and / or non-steroidal anti-inflammatory drugs NSAIDs ) or anticoagulant therapy for over consecutive 3 days within 2 weeks before screening.
6. With Glucose-6-phosphate dehydrogenase deficiency.
7. With retinal or visual field changes caused by 4-aminoquinoline compounds.
8. Being allergic to 4-aminoquinoline compounds.
9. Having evidence of Human Immunodeficiency Virus (HIV)/ hepatitis C virus(HCV)/ hepatitis B virus(HBV) infection (HIV antibody or HCV antibody is positive, HBV surface antigen is positive, or HBV surface antigen is negative but HBV-DNA indicating viral replication.
10. Glutamate transaminotransferase (ALT) or glutamate transaminase (AST) is higher than 1.5 times the upper limit of normal value (ULN), or total bilirubin or blood creatinine is higher than 1.2 times the ULN.
11. With liver cirrhosis or portal hypertension.
12. With evidence of malignant tumor activity, or receiving anti-tumor treatment within 5 years prior to the screening.
13. Participants being pregnant or lactating, or with potential fertility, reluctance to use effective contraception within the entire trial cycle and within 28 days after the end of the trial (or within 28 days after premature withdraw).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HCQ plus TPO-RA group; This group is experiment group. Participants will take eltrombopag for at least 24 weeks, the dose of eltrombopag is adjusted according to participants' platelet count, with HCQ twice a day for 1 year	Drug: Hydroxychloroquine Oral Tablet; Hydroxychloroquine is taken at the dose of 0.1g / dose, twice a day for 1 year, regardless of food intake.; Other Names: Hydroxychloroquine; Drug: Eltrombopag; Participants will take eltrombopag for at least 24 weeks, the dose of eltrombopag is adjusted according to participants' platelet count.; Other Names: Eltrombopag pill
Placebo Comparator: TPO-RA group; This group is control group. Participants will take eltrombopag for at least 24 weeks, the dose of eltrombopag is adjusted according to participants' platelet count.	Drug: Eltrombopag; Participants will take eltrombopag for at least 24 weeks, the dose of eltrombopag is adjusted according to participants' platelet count.; Other Names: Eltrombopag pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	The percentage of participants with platelet counts higher than 30×10^9/L and at least twice the baseline platelet count , for at least two consecutive tests (7 days apart).	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response rate	The percentage of participants with platelet counts higher than 100×10^9/L , for at least two consecutive tests (7 days apart).	1 year
Duration of response	Time from response to disease relapse (platelet count ≤ 30×10^9/L on any test or occurance of bleeding symptoms )	1 year
Durable response rate	Percentage of patients with complete remission lasting at least 6 months without any additional ITP-specific therapy	1 year
Platelet count at each visit	Average platelet count at each visit	1 year
Time to response	Time from starting treatment to response	4 weeks
Time to TPO-RA withdrawal	Time from starting treatment to TPO-RA withdrawal	24 weeks
Rate of TPO-RA withdrawal	Rate of participants who withdraw TPO-RA with platelet count over 30×10^9/L	24 weeks
The maximum dose of TPO-RA to attain response	The maximum dose of TPO-RA to attain response (platelet count over 30×10^9/L)	8 weeks
Response rate throughout the trial	The percentage of response participants (platelet counts higher than 30×10^9/L and at least twice the baseline platelet count ) at each visit	1 year
Once response rate throughout the trial	The percentage of once response participants (platelet counts higher than 30×10^9/L and over twice the baseline platelet count for at least one visit) throughout 1 year	1 year
WHO bleeding score	WHO bleeding score at each visit	1 year
Adverse reaction	Adverse reaction at each visit	1 year

Collaborators and Investigators

• Sponsor: Yunfeng Cheng
• Collaborators: Shanghai Zhongshan Hospital; Shanghai Jinshan Hospital; Macau University of Science and Technology Hospital; Zhongshan Qingpu Hospital, Fudan University; Zhongshan Wusong Hospital, Fudan University; Health and Humanity Research Centre, Hongkong; Dr. Stanley Ho Medical Foundation, Macau
• Investigators: Principal Investigator: Yunfeng Cheng, Shanghai Zhongshan Hospital

Publications and helpful links

General Publications

• Khellaf M, Chabrol A, Mahevas M, Roudot-Thoraval F, Limal N, Languille L, Bierling P, Michel M, Godeau B. Hydroxychloroquine is a good second-line treatment for adults with immune thrombocytopenia and positive antinuclear antibodies. Am J Hematol. 2014 Feb;89(2):194-8. doi: 10.1002/ajh.23609. Epub 2013 Nov 20.
• Neunert C, Terrell DR, Arnold DM, Buchanan G, Cines DB, Cooper N, Cuker A, Despotovic JM, George JN, Grace RF, Kuhne T, Kuter DJ, Lim W, McCrae KR, Pruitt B, Shimanek H, Vesely SK. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019 Dec 10;3(23):3829-3866. doi: 10.1182/bloodadvances.2019000966. Erratum In: Blood Adv. 2020 Jan 28;4(2):252.
• Mejdoub S, Hachicha H, Gargouri L, Feki S, Mahfoudh A, Masmoudi H. Antinuclear antibodies in children: clinical signification and diagnosis utility. Tunis Med. 2021 Octobre;99(10):980-984.
• Lambert MP, Gernsheimer TB. Clinical updates in adult immune thrombocytopenia. Blood. 2017 May 25;129(21):2829-2835. doi: 10.1182/blood-2017-03-754119. Epub 2017 Apr 17.

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2024
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: June 22, 2024
• First Submitted That Met QC Criteria: June 27, 2024
• First Posted (Actual): June 28, 2024

Study Record Updates

• Last Update Posted (Actual): June 28, 2024
• Last Update Submitted That Met QC Criteria: June 27, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Hematologic Diseases; Hemorrhage; Hemorrhagic Disorders; Blood Coagulation Disorders; Skin Manifestations; Blood Platelet Disorders; Thrombotic Microangiopathies; Purpura, Thrombocytopenic; Purpura; Cytopenia; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: B2024-027R2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: IPD information will become available starting 6 months after publication, for 1 year.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No