Randomized Study of Early Versus Delayed Epoetin Alfa Initiation in Lower-Risk Myelodysplastic Syndromes with Non-Transfusion-Dependent Anemia Without del(5q)

The primary objective of this study is to **randomly compare** the time to red blood cell (RBC) transfusion dependence in patients with lower risk myelodysplastic syndromes (MDS) who are non-RBC transfusion dependent and have anemia. The comparison is between patients receiving early onset of EPO alfa treatment at inclusion and those receiving delayed onset of EPO alfa treatment at the threshold chosen for RBC transfusions. This objective is clinically relevant as it aims to determine the optimal timing for initiating EPO alfa therapy to potentially delay the need for RBC transfusions, which can significantly impact patient management and quality of life.

Secondary objectives include:

• Comparing erythroid response according to IWG 2006 criteria after 12 weeks of EPO alfa treatment in the two randomized groups.
• Assessing the response duration to EPO alfa in both groups.
• Evaluating progression to higher risk MDS and/or acute myeloid leukemia (AML) in the two groups.
• Comparing the incidence of cardiovascular events between the groups.
• Assessing quality of life (QoL) using standard scales in both groups.
• Comparing overall survival between the two groups.
• Analyzing biological correlates and the ex vivo effect of EPO alfa on erythropoiesis, particularly on disease clonal architecture, using next-generation sequencing (NGS) analysis of somatic mutations. The hypothesis is that early EPO alfa treatment may favor less mutated erythropoiesis, potentially delaying disease progression.

The clinical trial involves **adult subjects** aged 18 years and older, diagnosed with low or intermediate-1 IPSS risk myelodysplastic syndromes (MDS) characterized by transfusion-independent anemia. The study population includes both male and female participants, with a focus on individuals who are not dependent on red blood cell (RBC) transfusions. Participants must have a hemoglobin level between 9.0 and 10.5 g/dl, which is at least 1 g/dl higher than the threshold set for initiating RBC transfusions, based on individual factors such as age and comorbidities. The trial includes individuals with a serum erythropoietin (EPO) level of less than 500 U/l and excludes those with other causes of anemia, such as iron deficiency or hypothyroidism. Participants are required to have a performance status of 2 or lower. The trial population was selected based on these criteria, and the sponsor has not provided information on the total number of participants. The study does not specify particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of early versus late onset of **epoetin alfa** treatment in patients with lower risk myelodysplastic syndromes (MDS) who have non-red blood cell (RBC) transfusion-dependent anemia and no 5q deletion. This is a randomized, controlled, double-blind trial aimed at comparing the time to RBC transfusion dependence between two groups: those receiving early treatment with epoetin alfa at inclusion and those receiving delayed treatment at a predetermined threshold for RBC transfusions. The trial is expected to run until February 28, 2025, with recruitment having commenced on February 12, 2018.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), diagnosis of MDS according to WHO 2016 criteria, and specific hemoglobin levels. Follow-up visits will be scheduled to monitor the primary endpoint, which is the time to RBC transfusion dependence, as well as secondary endpoints including erythroid response, quality of life, overall survival, and molecular biology correlations. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 24 months, depending on individual response and progression.

Participants may be withdrawn from the study early if they experience adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial will utilize a subcutaneous route for the administration of epoetin alfa, with a maximum daily dose of 60,000 units. The study is not categorized as low intervention and is classified as a Phase III therapeutic exploratory and confirmatory trial. The trial's methodology ensures rigorous assessment of the treatment's impact on delaying the need for RBC transfusions in the specified patient population.

The clinical trial involves the administration of **Epoetin Alfa**, marketed under the name EPREX 40000 UI/ml, as the experimental medication. This pharmaceutical product is presented as a **solution for injection** in a pre-filled syringe. The active substance, **Epoetin Alfa**, is a protein classified under the ATC code B03XA01, which corresponds to erythropoietin. The medication is intended for **subcutaneous use**. The maximum daily dose is 60,000 U units, with a total maximum dose of 60,000 U units over a treatment period of up to 24 weeks. The administration schedule is determined based on the trial's protocol, which compares early versus delayed onset of treatment in patients with lower-risk myelodysplastic syndromes (MDS) who are not dependent on red blood cell (RBC) transfusions and do not have the del 5q chromosomal abnormality.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of **Epoetin Alfa** to evaluate its efficacy in delaying the onset of RBC transfusion dependence in the specified patient population. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the treatment's impact on the clinical endpoints.

Efficacy in this clinical trial will be assessed by comparing the time to red blood cell (RBC) transfusion dependence between patients with early onset of **EPOETIN ALFA** treatment at inclusion and those with delayed onset at the threshold chosen for RBC transfusion. The primary endpoint is the time to RBC transfusion dependence, which will be measured and analyzed to determine the efficacy of early versus delayed treatment initiation.

Secondary endpoints include the International Working Group (IWG) 2006 erythroid response and its duration, quality of life (QoL), overall survival (OS), and molecular biology correlations. These parameters will be evaluated using appropriate validated scales and laboratory tests. The trial is designed to provide a comprehensive assessment of the therapeutic effects of **EPOETIN ALFA** in patients with lower risk myelodysplastic syndromes (MDS) who are non-RBC transfusion dependent and have anemia without the 5q deletion.