A Randomized Trial of rhTPO Versus Placebo for Low/Intermediate-1 Risk MDS With Thrombocytopenia

Study Overview
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Brief Summary
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Myelodysplastic syndrome (MDS) is a kind of clonal myeloid tumor. The major manifestation is decrease of tri-lineages of blood due to ineffective and abnormal hematopoiesis, some of which can progress to acute myeloid leukemia. According to the international prognosis scoring system (IPSS) of MDS, about 10% low/intermediate risk-1 MDS patients have severe thrombocytopenia (PLT < 30 × 109/ L). These patients have both decreased platelet count and platelet dysfunction, resulting in a high risk of bleeding. In the new prognostic score, such as IPSS-r, the degree of thrombocytopenia is regarded as a poor prognostic factor. Platelet transfusion is mainly used in the treatment of this kind of patients. The indications of transfusion include bleeding events or severe platelet count reduction (< 10 × 109 / L). However, platelet transfusion can only lead to short-term platelet elevation, while repeated transfusion increases the possibility of infection and ineffective platelet transfusion. TPO is a newly discovered hematopoietic promoting factor, which can specifically bind to the TPO receptor on the cell and participate in the regulation of proliferation, differentiation, maturation and division of megakaryocyte to form functional platelet. The efficacy and safety of the TPO receptor agonists eltrombopag and romiplostim in the treatment of thrombocytopenia in low/intermediate risk-1 MDS patients have been successfully confirmed in foreign studies. Recombinant human thrombopoietin (rhTPO) is also a kind of a TPO receptor agonists which is highly specific platelet stimulating factor. At present, there is no large report on the application of rhTPO in such patients. The purpose of this study is to explore the short-term and long-term therapeutic effect and safety of rhTPO on low/intermediate risk-1 MDS patients.

Official Title
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A Randomized Trial of Recombinant Human Thrombopoietin Versus Placebo for Low/Intermediate-1 Risk Myelodysplastic Syndromes With Thrombocytopenia

Conditions
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Low/Intermediate Risk-1 MDS

Intervention / Treatment
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* Drug: Danazol + rhTPO (recombinant human thrombopoietin injection)
* Drug: Danazol + sodium chloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed MDS, IPSS low / intermediate risk-1 In the 4 weeks before inclusion, the average value of platelets was ≤ 30 × 10e9 / L, or < 50 × 10e9 / L with bleeding events Patients with EPO due to anemia and G-CSF due to severe neutropenia can be included, and the dosage will not change during trial Baseline liver and kidney function: ALT / ASL within 3 times normal upper limit, TBIL within 2 times normal upper limit, and creatinine within 2 times normal upper limit ECOG 0-2 points Able to sign informed consent Exclusion Criteria: Pregnant or lactating IPSS intermediate risk-2 / high risk MDS More than 5% of myeloblasts in bone marrow Myelofibrosis Previous transplantation or ATG treatment within 6 months Previous use of IL-11, TPO or other TPO receptor agonists Active infection or tumor Thromboembolic or hemorrhagic disease Serious heart disease, including unstable angina, congestive heart failure, arrhythmia, 1-year history of myocardial infarction Intracranial hemorrhage within 4 weeks

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: TPO treatment group<br>Danazol 0.2g tid po+rhTPO (recombinant human thrombopoietin injection) 300U/kg/d×14d si every month (stop when PLT≥100×10e9/L or increased more than 50×10e9/L), total course 6 months | Drug: Danazol + rhTPO (recombinant human thrombopoietin injection)<br>* subcutaneous injection, 300U/kg/d×14d every month，stop if the PLT≥100×10e9/L or increased >50×10e9/L, total course is 6 months<br>|
| Placebo Comparator: control<br>Danazol 0.2g tid po+ control (sodium chloride)×14d si every month, total course 6 months | Drug: Danazol + sodium chloride<br>* Danazol 0.2g tid po+ control (sodium chloride)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate | overall response rate of platelet | 1 year | 
| rate of side effects | rate of all kinds of side effects | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WHO bleeding score | to evaluate frequency and severity of bleeding | 1 year | 
| change of platelet transfusion | the frequency and amount of platelet transfusion | 1 year | 
| onset time for overall response | onset time for complete and partial response | through study completion, an average of 1 year | 
| duration of overall response | during time for complete and partial response | through study completion, an average of 1 year | 
| incidence of TPO antibody | rate of presence of TPO antibody | 1 year | 
| life quality for MDS patients | life quality for MDS patients by QoL-E questionaire | 1 year | 
| the increased number of myeloblasts in bone marrow and peripheral blood | the increased number of myeloblasts in bone marrow and peripheral blood | 1 year | 
| incidence of progression to high-risk MDS or leukemia | incidence of progression to high-risk MDS or leukemia | 1 year |