β-thalassemia is one of the most common inherited hemoglobinopathies worldwide and a major public health issue that severely impacts birth quality, human health, and social progress. Currently, there are limited clinical drugs specifically designed to treat patients with β-thalassemia. This clinical trial aims to evaluate the efficacy and safety of luspatercept combined with low-dose thalidomide compared with luspatercept alone in patients with thalassemia. Key questions to be answered include:

• Does luspatercept combined with low-dose thalidomide reduce the transfusion burden in patients with β-thalassemia major?
• What medical problems may occur when patients receive luspatercept combined with low-dose thalidomide? In this clinical trial, participants were randomly assigned in a 1:1 ratio to either an intervention group (luspatercept combined with low-dose thalidomide) or a control group (luspatercept combined with placebo) using a central randomization system. The clinical efficacy and safety of the two groups were evaluated. The primary outcome measure was the clinical efficacy of luspatercept combined with low-dose thalidomide in reducing the transfusion burden in patients with β-thalassemia major.

This is a prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the clinical efficacy and safety of luspatercept combined with low-dose thalidomide versus luspatercept combined with placebo in adult patients with β-thalassemia requiring regular red blood cell transfusions.

The study is divided into the following phases: screening/run-in period, double-blind treatment period, and follow-up period. Participants are centrally randomized in a 1:1 ratio to either the intervention group or the control group. The primary objective is to compare the clinical response rate between the intervention group (luspatercept combined with low-dose thalidomide) and the control group (luspatercept combined with placebo) in adult patients with transfusion-dependent β-thalassemia. Clinical response is defined as the proportion of subjects achieving a reduction in red blood cell (RBC) transfusion burden by ≥50% and at least 2 units during weeks 13-24 after randomization compared with the baseline period (12 weeks prior to randomization). Secondary objectives mainly include assessments of other clinical efficacy indicators, iron metabolism, hemolysis, as well as the incidence of adverse events.

Statistical analyses in this clinical study are based on the Intention-To-Treat (ITT) principle. Subgroup analyses of the primary endpoint are planned according to baseline transfusion burden (low, medium, and high transfusion burden groups).

The study plans to consecutively enroll 78 participants across eight research centers: the First Affiliated Hospital of Guangxi Medical University, Liuzhou People's Hospital, Liuzhou Worker's Hospital, Yulin First People's Hospital, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise People's Hospital,Yunnan Provincial First People's Hospital and Southern Medical University Shenzhen Hospital. During the screening and run-in period, patients with severe β-thalassemia major (β-TM) who are scheduled to receive luspatercept combined with low-dose thalidomide or luspatercept monotherapy are invited to participate. Written informed consent is provided to potential subjects, along with a detailed explanation of the study content. Written informed consent from the subject (or their legal representative) must be obtained before any study-specific procedures are conducted. After signing the informed consent form, baseline data are collected. During the double-blind treatment period, the intervention group receives luspatercept combined with low-dose thalidomide, while the control group receives luspatercept combined with placebo. Both groups may receive best supportive care, including RBC transfusions, iron chelators, antiplatelet therapy, antibiotic therapy, antiviral and antifungal therapy, and/or nutritional support as needed. During the follow-up period, subjects are followed up at weeks 12, 24, 36, and 48. Data on physical examination, vital signs, hematological tests, clinical biochemistry, transfusion status, iron parameters, quality of life, concomitant treatments, subject compliance, and adverse events are collected and recorded in detail for further analysis of clinical efficacy and safety.

Inclusion Criteria:

• Age ≥ 18 years, regardless of gender;
• Patients with transfusion-dependent β-thalassemia;
• Intended treatment with rotecept combined with low-dose thalidomide or rotecept alone;
• Requires regular red blood cell transfusions (6-30 RBC units (International Units) within 24 weeks prior to randomization, with a transfusion-free interval of ≤ 42 days);
• ECOG performance status 0-1;
• Patients (or legal guardians) voluntarily participate in the study and provide signed informed consent.

Exclusion Criteria:

• A diagnosis of α-thalassemia minor, Hb Bart's edema, hemoglobin S/β-thalassemia, or myelodysplastic anemia (combination of β-thalassemia and α-thalassemia is permitted);
• Anemia related to nutritional deficiency, anemia of chronic disease, autoimmune hemolytic anemia, or any other hemolytic anemia (e.g., severe G6PD deficiency, pyruvate kinase deficiency);
• A bleeding disorder manifesting as frequent bleeding (e.g., menorrhagia, epistaxis, coagulopathy);
• Hemolysis unrelated to thalassemia within the past 8 weeks, such as after use of hemolytic-inducing medications (e.g., antimalarials, nonsteroidal anti-inflammatory drugs [NSAIDs]);
• Use of long-term anticoagulant therapy, unless discontinued at least 28 days before randomization. Prophylactic anticoagulant therapy for surgery or high-risk procedures, as well as low-molecular-weight heparin and long-term aspirin therapy for superficial venous thrombosis, are permitted.
• Use of thalidomide alone, erythropoiesis-stimulating drugs (ESA), or hydroxyurea within the past 24 weeks.
• Use of long-term systemic glucocorticoids within the past 12 weeks.
• Use of cytotoxic drugs, immunosuppressants, or other investigational drugs within the past 28 days.
• HIV positive and/or active HCV or HBV infection.
• Hepatic and renal insufficiency (liver insufficiency, i.e., aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≥3× upper limit of normal (ULN); renal insufficiency, i.e., serum creatinine ≥3× upper limit of normal (ULN) or creatinine clearance less than 30). mL/min), history of malignancy (unless cured and/or with no known active disease);
• Women who are pregnant, plan to become pregnant during the study, or are breastfeeding;
• Previous thalassemia gene therapy or hematopoietic stem cell transplantation (HSCT);
• Platelet count < 70 × 109/L, if not associated with hypersplenism, or platelet count > 1,000 × 109/L;
• Other conditions deemed unsuitable for participation in this clinical trial by the investigator.

This trial was conducted using a double-blind approach, meaning that neither the researchers nor the subjects knew the group assignments or the interventions they were receiving. Furthermore, the outcome assessors were also blinded, objectively evaluating the outcome measures without knowing the groups assigned to the subjects.