ELEMENT-MDS: A Study to Compare the Efficacy and Safety of Luspatercept in Participants With Myelodysplastic Syndrome (MDS) and Anemia Not Receiving Blood Transfusions

Study Overview
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Brief Summary
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The purpose of the study is to compare the efficacy and safety of Luspatercept vs epoetin alfa in the treatment of anemia in adults due to IPSS-R very low, low, intermediate-risk MDS in ESA-naïve participants who are non-transfusion dependent (NTD).

Official Title
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A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) vs Epoetin Alfa for the Treatment of Anemia Due to Revised International Prognostic Scoring System (IPSS-R) Very Low, Low, or Intermediate-Risk Myelodysplastic Syndrome (MDS) in Erythropoiesis-Stimulating Agent (ESA)-Naive Participants Who Are Non-Transfusion Dependent (NTD): The ELEMENT-MDS Trial

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Biological: Luspatercept
* Biological: Epoetin Alfa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has documented diagnosis of MDS according to World Health Organization (WHO) 2016 that meet IPSS-R classification of very low, low, or intermediate-risk disease, (intermediate-risk of ≤ 3.5 IPSS-R score) confirmed via bone marrow aspirate and: i) < 5% blasts in bone marrow and < 1% blasts in peripheral blood. Participant is not transfusion dependent (NTD) based on IWG2018 criteria Participant has never received treatment with an erythropoiesis stimulating agent (ESA) Participant has a baseline endogenous serum erythropoietin (sEPO) level of ≤ 500 U/L. Participant has symptoms of anemia: i) Participant records a severity score of moderate or greater on at least 1 PGI-S item of fatigue, weakness, shortness of breath, or dizziness performed during the screening period. Participant has a mean baseline Hb concentration prior to randomization of ≤ 9.5 g/dL. Mean Hb is defined as the mean of all central/ local/ pretransfusion available Hb measurements during the 16 weeks prior to randomization (with a minimum of 2 measurements at least 1 week apart). Only Hb levels > 21 days following a transfusion are acceptable. The last measurement must be within 35 days of randomization. Exclusion Criteria: Participant with secondary MDS (that is, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases). Participant with known history of diagnosis of AML. Participant with history of cerebrovascular accident (including ischemic, embolic, and hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous thrombosis (including proximal and distal), pulmonary or arterial embolism, arterial thrombosis, or other venous thrombosis within 6 months prior to randomization. Participant with a history of pure red cell aplasia and/or antibody against erythropoietin. Note: Other protocol-defined inclusion/exclusion criteria apply.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Luspatercept<br> | Biological: Luspatercept<br>* Specified dose on specified days<br>* Other names: Reblozyl®;|
| Active Comparator: Epoetin Alfa<br> | Biological: Epoetin Alfa<br>* Specified dose on specified days<br>* Other names: BINOCRIT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with lower-risk non-transfusion dependent myelodysplastic syndromes (NTD-MDS) who converted to Transfusion Dependence (TD) during any continuous 16-week interval within the 96-week treatment period | TD is defined as ≥ 3 red blood cells (RBC) units/16 weeks assessed by International Working Group (IWG) 2018. | Up to Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with an increase from baseline in mean Hb values of ≥ 1.5 grams/deciliter (g/dL) in any continuous 16-week interval within the 48 week Treatment Period in the absence of transfusion |  | Up to Week 48 | 
| Number of participants with an increase from baseline in mean Hb values of ≥ 1.5 g/dL in any continuous 24-week interval within the 48-week and 96-week treatment period in the absence of transfusion |  | Up to Week 48 | 
| Number of participants with an increase from baseline in mean Hb values of ≥ 1.5 g/dL in any continuous 24-week interval within the 48-week and 96-week treatment period in the absence of transfusion |  | From Week 49 to Week 96 | 
| Number of participants with an increase from baseline in mean Hb values of ≥ 1.5 g/dL in any continuous 24-week interval within the 48-week and 96-week treatment period in the absence of transfusion |  | Up to Week 96 | 
| Number of participants with an increase from baseline in mean Hb values of ≥ 1.0 g/dL in any continuous 24-week interval within the 48-week and 96-week treatment period in the absence of transfusion |  | Up to Week 48 | 
| Number of participants with an increase from baseline in mean Hb values of ≥ 1.0 g/dL in any continuous 24-week interval within the 48-week and 96-week treatment period in the absence of transfusion |  | From Week 49 to Week 96 | 
| Number of participants with an increase from baseline in mean Hb values of ≥ 1.0 g/dL in any continuous 24-week interval within the 48-week and 96-week treatment period in the absence of transfusion |  | Up to Week 96 | 
| Mean Hb change over fixed 24-week periods compared to the baseline Hb |  | Baseline, Week 24, Week 48, Week 72, Week 96 | 
| Number of participants with an increase from baseline in mean Hb values of ≥ 1.5 g/dL in any continuous 16-week interval within the 96-week treatment period in the absence of transfusion |  | Up to Week 96 | 
| Number of participants with TD by week 48 |  | Up to Week 48 | 
| Time to TD (IWG 2018 defined as ≥ 3 RBC units/16 weeks) during any continuous 16-week interval until the end of study |  | Up to 5 years | 
| Time from first Luspatercept dose to first RBC transfusion |  | Up to 5 years | 
| Duration of median hematologic improvement in erythroid response(mHI-E) in participants with an increase from baseline in mean Hb values of ≥1.5g/dL in any continuous 16-week interval within 48-week treatment period in absence of transfusion |  | Up to Week 48 | 
| Duration of median hematologic improvement in erythroid response(mHI-E) in participants with an increase from baseline in mean Hb values of ≥1.5g/dL in any continuous 16-week interval within 96-week treatment period in absence of transfusion |  | Up to Week 96 | 
| Time from first dose to first day of response (increase in mean Hb values of ≥ 1.5 g/dL in any continuous 16-week interval within the 48-week Treatment Period in the absence of transfusion) |  | Up to Week 48 | 
| Time from first dose to first day of response (increase in mean Hb values of ≥ 1.5 g/dL in any continuous 16-week interval within the 96-week Treatment Period in the absence of transfusion) |  | Up to Week 96 | 
| Number of participants with RBC transfusion independence over at least a consecutive 24-week period |  | Up to 5 years | 
| Number of transfusions |  | Up to 5 years | 
| Number of transfusions visits/units |  | Up to 5 years | 
| Change from baseline in subscales of self-reported health-related quality-of-life (HRQoL) assessed by the Functional Assessment of Cancer Therapy - Anemia (FACT-An) |  | Baseline, Up to 5 years | 
| Change from baseline in self-reported HRQoL assessed by the European quality of life questionnaire 5-dimension (EQ-5D-5L) |  | Baseline, Up to 5 years | 
| Number of participants with adverse events (AEs) |  | Up to Week 102 | 
| Number of participants with antidrug antibody (ADA) (positive or negative) |  | Up to Week 102 | 
| Pharmacokinetics (PK): Serum concentration |  | Up to Week 96 | 
| PK: Area under the plasma concentration time curve (AUC) |  | Up to Week 96 | 
| Number of participants with a platelet response at Week 24, Week 48 and Week 96 | Platelet response is defined as an increase from baseline in number of platelets to ≥ 30 × 10^9/L at Week 24, Week 48 and Week 96. | Up to Week 96 | 
| Number of participants with a neutrophil response at Week 24, Week 48 and Week 96 | Neutrophil response is defined as an absolute increase from baseline of > 0.5 × 10^9/L neutrophils at Week 24, Week 48 and Week 96. | Up to Week 96 | 
| Number of participants with acute myeloid leukemia (AML) progression |  | Up to 5 years | 
| Time to AML progression |  | Up to 5 years | 
| Number of participants with high risk myelodysplastic syndromes (MDS) progression |  | Up to 5 years | 
| Time to high-risk MDS progression |  | Up to 5 years | 
| Time from date of randomization up to death due to any cause |  | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Luspatercept, BMS-986346, ACE-536, Myelodysplastic Syndrome, Epoetin alfa, Erythropoietin stimulating agent (ESA), Myelodysplastic Syndromes (MDS), Anaemia