Efficacy and Safety in Transfusion Independent Non-severe Aplastic Anemia

Study Overview
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Brief Summary
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Aplastic anemia (AA) is a rare bone marrow failure disease characterized by bone marrow hypocellularity and peripheral blood pancytopenia. AA is divided into severe AA (SAA) and non-severe AA (NSAA) based on the degree of cytopenia. The first line therapy for SAA or transfusion dependent NSAA is either immunosuppression therapy (IST) or hematopoietic stem cell transplantation (HSCT). Little attention has been paid to patients with anemia but not transfusion dependent, whose quality of life is significantly impaired due to the anemia and other complications.

Detailed Description
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Recombined human erythropoietin (rhEPO) has been shown to increase the erythroid response and response rate when combined with IST for patients with newly diagnosed AA, either SAA or NSAA. Different from rhEPO, luspatercept is a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands and enhances late-stage erythropoiesis, and has been shown the promising efficiency in the erythropoiesis in patients with lower risk myelodysplastic syndrome (MDS) in the phase II and III clinical trials. This randomized control study aimed to compare the 6-month efficacy and safety of the combination of luspatercept and ciclosporin versus ciclosporin monotherapy in patients with newly diagnosed transfusion independent NSAA.

Official Title
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A Randomized, Case Controlled Clinical Trial Evaluating the Efficiency and Safety of Luspatercept Plus Ciclosporin Versus Ciclosporin in Newly Diagnosed Transfusion Independent Non-severe Aplastic Anemia (NSAA).

Conditions
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Aplastic Anemia

Intervention / Treatment
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* Drug: Luspatercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age≥18 year-old; hemoglobin level between 60g/L 10 g/dL; newly diagnosed patients have at least one of the followings: #absolute neutrophil count <1.5×109/L, #platelet count < 30×109/L, # hemoglobin level < 100g/L; with normal baseline liver and kidney function; with no active infection; are not pregnant or nursing; agree to sign consent forms; Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Exclusion Criteria: Congenital aplastic anemia; Presence of chromosomal aberration; Evidence of a clonal hematologic bone marrow disorder (MDS, AML) on cytogenetics; Presence with PNH clone ≥50%; Patients received HSCT before; Uncontrolled infection or bleeding with standard treatment; Allergic to luspatercept CsA or accessories; HIV, HCV or HBV active infection or liver cirrhosis or portal hypertension; Patient with QTcF (Fridericia's QT correction formula) at screening <450 msec, or<480 msec with bundle branch block, as determined via the mean of a triplicate ECG and assessed at site, unstable angina pectoris, uncontrolled hypertension(>180/100mmHg)#pulmonary artery hypertension; Have any concomitant malignancies within 5 years expect for local basal cell carcinoma of the skin; Past history of thromboembolic event, heart attack or stroke (including anti-phospholipid antibody syndrome) and current use of anticoagulants; Pregnant or nursing (lactating) woman; Have attended other clinical trials within 3 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Interventional Model Description: Ciclosporin soft capsules（25mg） are produced by North China pharmaceutical Group Corporation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: efficiency and safety in luspatercept plus ciclosporin<br>luspatercept is at a dose of 1.0 mg per kilogram of body weight, administered subcutaneously every 3 weeks，and ciclosporin is at a dose of 3 5mg/kg /day for at least 6 months. | Drug: Luspatercept<br>* Patients in each group will be treated for at least 6 months and continue the treatment for an additional 6 months unless disease progress or have intolerable side effects.<br>* Other names: ciclosporin;|
| Active Comparator: controll group in ciclosporin alone<br>ciclosporin is at a dose of 3 5mg/kg /day for at least 6 months. | Drug: Luspatercept<br>* Patients in each group will be treated for at least 6 months and continue the treatment for an additional 6 months unless disease progress or have intolerable side effects.<br>* Other names: ciclosporin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate (ORR) | Overall Response Rate (ORR) Defined as the Number of Participants Who Met the Criteria of Either Complete Response (CR) or Partial Response (PR); HR defined as a hemoglobin increase from baseline of ≥1.5 g/dL for ≥2 weeks (in the absence of RBC transfusions) | 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic response-erythroid（HR-E) | HR is defined as a hemoglobin increase from baseline of ≥1.5 g/dL for ≥2 weeks (in the absence of RBC transfusions | 6 month | 
| side effects | Safety analyses include assessments of the incidence and severity of adverse events; all adverse events that occurred or worsened during the treatment period will be reported, as well as adverse events that occurred later but are considered by the investigator to be related to the trial drug. | 1 year | 
| predictive factors | Predictors analyses will evaluate the relationship between the effect of these two treatments with molecular mutations PIGA and BCOR and BCORL1 and EPO level. | 6 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSAA, luspatercept, ORR, non-transfusion dependent