A Study to Determine the Efficacy and Safety of Luspatercept in Adult Participants and to Evaluate the Safety and Pharmacokinetics in and Adolescent Participants With Alpha (α)-Thalassemia

Phase 2RecruitingNCT05664737

Bristol-Myers Squibb249 enrolled

Overview

The purpose of the study is to evaluate the efficacy and safety of luspatercept plus best supportive care (BSC) vs placebo plus BSC on anemia in adult participants with α-thalassemia hemoglobin H (HbH) disease and determine the safety and drug levels in adolescent participants.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

249

Conditions

Anemia

Interventions

LuspaterceptBIOLOGICAL

Specified dose on specified days

PlaceboDRUG

Specified dose on specified days

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: * Adult participant≥ 18 years with documented diagnosis of A-Thal HbH disease with Transfusion dependence defined as:. 1. TD participant: ≥ 6 RBC units during the 24 weeks prior to randomization. 2. NTD participant:\< 6 RBC units during the 24 weeks prior to randomization(transfusion due to conditions other than A-Thal will not be considered)and, RBC transfusion-free during at least 8 weeks prior to randomization(unless transfusion was required to treat an acute medical condition other than A-Thal) and, mean baseline Hb ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4 weeks prior to randomization; hemoglobin values within 21 days post-transfusion will be excluded. * Adult participant has Eastern Cooperative Oncology Group (ECOG) 34 score of 0 or 1. * Adolescent participant 12 years to \< 18 years with documented diagnosis of A-Thal HbH disease with transfusion dependence defined as:. 1. TD participant: ≥ 4 RBC events during the 24 weeks prior to enrollment and, no transfusion-free period for \> 56 days during the 24 weeks prior to enrollment. Participants must have a history of regular transfusions for at least 2 years. 2. NTD participant:\< 4 RBC events during the 24 weeks prior to enrollment and RBC transfusion-free during at least 8 weeks prior to enrollment and, mean baseline Hb ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4 weeks prior to enrollment, hemoglobin values within 21 days post-transfusion will be excluded. 3. Participant has Karnofsky (age ≥16 years) or Lansky (age \< 16 years) performance status score ≥ 50 at screening. Key Exclusion Criteria: * Medical Conditions: Diagnosis of A-ThalTrait, Hb Bart hydrops, ATRx A-Thal, hemoglobin S/β-thalassemia, myelodysplasia subtype anemia, or with HbE homozygous beta gene mutation. Anemia related to nutritional deficiency, anemia of chronic disease, autoimmune hemolytic anemia, or any other hemolytic anemias. Undergone episodes of hemolysis not related to A-Thal within the 8 weeks prior to randomization. * Participant has deep vein thrombosis (DVT), stroke or other thromboembolic event(s) (except clogged indwelling catheter) requiring medical intervention ≤ 24weeks prior to randomization. * Participant has uncontrolled hypertension. Controlled hypertension for this protocol is considered: blood pressure value corresponding to ≤Grade 1 according to NCI CTCAE Version 5.0. with or without pharmacological treatment. * Reproductive Status: Women who are pregnant, plan to get pregnant during the study, or who are breastfeeding. * Prior/Concomitant: Undergone HSCTs or gene therapy (candidates for HSCT or gene therapy with waiting period of ≥ 12 months are eligible). * Use of hydroxyurea treatment ≤ 12 weeks prior to enrollment for NTD participants and ≤ 24 weeks for TD participants. * Participant who has extramedullary hematopoiesis (EMH) complications requiring treatment to control the growth of EMH mass(es) during the screening period. * Any medical or psychiatric condition (including active infections, recent surgery, sequelae of diseases or interventions, clinically significant laboratory abnormalities or concurrent treatment) that in the opinion of the investigator would put the participant at unacceptable risk of participating in the study or that could affect interpretability of data. * Other protocol-defined inclusion/exclusion criteria apply.

Locations (36)

Outcomes

Primary Outcomes

Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units during any continuous 12 weeks during Week 13-48 compared to 12-week interval immediately prior to date of first dose

Adult TD Cohort

Time frame: Up to Week 48

Number of participants with an increase from baseline of ≥ 1.0 grams (g)/decilitre (dL) in mean hemoglobin (Hb) values over the continuous 12-week interval from Week 13 to Week 24 in the absence of RBC transfusion

Adult NTD Cohort

Time frame: Up to Week 24

Dose-limiting toxicities (DLTs) defined as observance of ≥ Grade 3-related hemolytic crises or ≥ Grade 3-related event outside of the known safety profile occurring within the 21 days from their first dose of study therapy

Adolescent TD and NTD Cohorts

Time frame: Up to Week 3

Number of participants with adverse events (AEs)

Adolescent TD and NTD Cohorts

Time frame: Up to 8.5 years

Pharmacokinetics (PK): Serum concentration of Luspatercept

Adolescent TD and NTD Cohorts

Time frame: Up to Week 102

Secondary Outcomes

Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units during any continuous 24-week interval on treatment compared to 24-week interval immediately prior to date of first dose

Adult TD Cohort

Time frame: Up to Week 108

The longest duration with ≥ 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units

Central Contacts

BMS Clinical Trials Contact Center www.BMSClinicalTrials.com

CONTACT

855-907-3286 Clinical.Trials@bms.com

First line of the email MUST contain NCT # and Site #.

CONTACT

Data from ClinicalTrials.gov

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Local Institution - 0008

Halifax, Nova Scotia, Canada

WITHDRAWN

Sun Yat-sen Memorial Hospital, Sun Yat-Sen University

Guangzhou, GD, China

RECRUITING

Nanfang Hospital of Southern Medical University

Guangzhou, GD, China

RECRUITING

The First People's Hospital of Foshan

Foshan, Guangdong, China

RECRUITING

Maoming People's Hospital

Maoming Shi, Guangdong, China

RECRUITING

Shenzhen Second People's Hospital

Shenzhen Shi, Guangdong, China

RECRUITING

Liuzhou People's Hospital

Liuchow, Guangxi, China

RECRUITING

People's Liberation Army The 923rd Hospital

Nanning, GX, China

RECRUITING

Local Institution - 0011

Haikou, Hainan, China

ACTIVE_NOT_RECRUITING

Local Institution - 0012

Kunming, Yunnan, China

COMPLETED

...and 26 more locations

Time frame: Up to Week 108

Number of RBC transfusion units from week 1 to week 48

Adult and Adolescent TD Cohorts

Time frame: Up to Week 48

Change from baseline in hemoglobin in the absence of transfusion at Week 24

Adult and Adolescent NTD Cohorts

Time frame: Up to Week 24

The longest duration of an increase from baseline of ≥ 1.0 g/dL in mean hemoglobin values starting from Week 13 in the absence of transfusion

Adult NTD Cohort

Time frame: Up to Week 108

Time Duration with an increase from baseline of ≥ 1.0 g/dL in hemoglobin values in the absence of transfusion within 48 weeks

Adult NTD Cohort

Time frame: Up to Week 48

Number of participants with an increase from baseline of ≥1.0 g/dL in mean Hb values over the continuous 12- week interval in the absence of transfusion

Adult NTD Cohort

Time frame: Up to Week 24

≥ 3 Increase from Baseline in Functional Assessment of Cancer Therapy Anemia Fatigue Subscale (FACT-An FS) Score from Baseline to the period from Week 13 to Week 24

Adult NTD Cohort

Time frame: Up to Week 24

Number of participants with AEs

Adult and Adolescent TD and NTD Cohorts

Time frame: Up to 5 years

Number of participants with laboratory abnormalities

Adult TD and NTD Cohorts

Time frame: Up to 5 Years

Number of participants with immunogenicity

Adult TD and NTD Cohorts

Time frame: Up to 5 Years

Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden during any continuous 24-week interval within 48 weeks compared to the 24-week interval immediately prior to the date of first dose

Adult TD Cohort

Time frame: Up to Week 48

Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden during any continuous 12-week interval compared to the 12-week interval immediately prior to the date of first dose

Adult TD Cohort

Time frame: Up to Week 108

Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden from Week 13 to Week 24 and Week 37 to Week 48 compared to the 12-week interval immediately prior to the date of first dose

Adult TD Cohort

Time frame: Up to Week 48

Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden from Week 1 to Week 24 and Week 25 to Week 48 compared to the 24-week interval immediately prior to the date of first dose

Adult TD Cohort

Time frame: Up to Week 48

Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden from Week 13 to Week 24 and Week 37 to Week 48 compared to the 12-week interval immediately prior to the date of first dose

Adult TD Cohort

Time frame: Up to Week 48

Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden from Week 1 to Week 24 and Week 25 to Week 48 compared to the 24-week interval immediately prior to the date of first dose

Adult TD Cohort

Time frame: Up to Week 48

Change from baseline in total RBC units transfused from Week 1 to Week 24, Week 25 to Week 48, and Week 1 to Week 48

Adult TD Cohort

Time frame: Up to Week 48

The longest duration of RBC transfusion-free period for participants who achieve transfusion-free period of ≥ 12 weeks

Adult TD Cohort

Time frame: Up to Week 108

The longest duration of reduction in transfusion burden for participants who achieve a response (rolling 12-week and 24-week response, both for ≥ 33% and ≥ 50% reduction)

Adult TD Cohort

Time frame: Up to Week 108

Time from first dose to first day of response (rolling 12-week and 24-week response, both for ≥ 33% and ≥ 50% reduction)

Adult TD Cohort

Time frame: Up to Week 108

Change from baseline in number of transfusion events at Week 48

Adult TD Cohort

Time frame: Up to Week 48

Number of participants who achieve RBC transfusion-free period of any continuous ≥ 12 weeks during treatment

Adult and Adolescent TD and NTD Cohorts

Time frame: Up to Week 108

Number of participants who achieve RBC transfusion-free period of any continuous ≥ 24 weeks during treatment

Adult and Adolescent TD and NTD Cohorts

Time frame: Up to Week 108

Time to first transfusion

Adult and Adolescent NTD Cohorts

Time frame: Up to Week 108

Number of transfusions

Adult NTD Cohort

Time frame: Within 48 Weeks

Number of transfusion visits/units

Adult NTD Cohort

Time frame: Within 48 Weeks

Change from baseline in mean hemoglobin values over the continuous 12-week interval from Week 13 to Week 24 and Week 37 to Week 48 in the absence of transfusions

Adult TD and NTD Cohorts

Time frame: Up to Week 48

Number of participants achieving an increase from baseline of ≥1.0g/dL or ≥1.5g/dL in mean Hb values in absence of transfusions from Week 13 to Week 24, Week 37 to Week 48 and during any continuous 12-week window within 24 weeks and 48 weeks

Adult NTD Cohort

Time frame: Up to Week 48

Time from first to last Hb measurement with increase from baseline by ≥ 1.0 g/dL

Adult NTD Cohorts

Time frame: Up to Week 108

Time to the first increase from baseline of ≥ 1.0 g/dL in mean Hb value

Adolescent NTD Cohort

Time frame: Up to Week 48

Number of participants who achieve an increase in mean Hb of >10g/dL values during any continuous 12-week and 24-week interval within 48 weeks in the absence of transfusions

Adult NTD Cohort

Time frame: Up to Week 48

Change from baseline in self-reported health-related quality of life (HRQoL) assessed by physical component summary (PCS) and mental component summary (MCS) of 36-item short-form health survey version2 (SF-36v2) at Week 24 and Week 48

Adult TD and NTD Cohorts

Time frame: Up to Week 48

Change from baseline in non-transfusion dependent β-thalassemia patient-reported outcome (NTDT-PRO) Tiredness/weakness (T/W) and shortness of breath (SoB) domain scores from Week 13 to Week 24 and from Week 37 to Week 48

Adult NTD Cohort

Time frame: Up to Week 48

Change from baseline in FACT-An FS Score at Week 24 and Week 48

Adult NTD Cohort

Time frame: Up to Week 48

Change from baseline in Functional Assessment of Cancer Therapy Anemia Anemia Subscale (FACT-An AS) at Week 24 and Week 48

Adult NTD Cohort

Time frame: Up to Week 48

Number of participants with at least one hemolytic crisis

Adult TD and NTD Cohorts

Time frame: Up to Week 108

Rate of hemolytic crises

Adult TD and NTD Cohorts

Time frame: Up to Week 108

Time to first hemolytic crisis

Adult TD and NTD Cohorts

Time frame: Up to Week 108

Time to second hemolytic crisis

Adult TD and NTD Cohorts

Time frame: Up to Week 108

Change from baseline in hemolysis markers at Week 24 and Week 48

Adult TD and NTD Cohorts:

Time frame: Up to Week 48

Change from baseline in the 6-minute walk test (6MWT) distance at Week 24 and Week 48

Adult NTD Cohort

Time frame: Up to Week 48

Pharmacokinetics (PK): Serum concentration of Luspatercept

Adult and Adolescent TD and NTD Cohorts

Time frame: Up to Week 108

Percent Change from Baseline in Biomarkers for Erythropoiesis at Week 84

Adult TD and NTD Cohorts The biomarkers for erythropoiesis to be evaluated include Hb variants including hemoglobin H (HbH), sTfR1, erythropoietin (EPO), growth differentiation factor (GDF11), GDF8, GDF15. The change will be measured as a percentage of change from baseline for all the biomarkers.

Time frame: Baseline, Week 84

Percent Change from Baseline in Biomarkers and Parameters for Iron Homeostasis at Week 84

Adult TD and NTD Cohorts The biomarkers and parameters for iron homeostasis to be evaluated include hepcidin, erythroferrone (ERFE), serum ferritin, liver iron concentration (LIC), myocardial iron, iron chelation therapy (ICT). The change will be measured as a percentage of change from baseline for all the biomarkers.

Time frame: Baseline, Week 84

Change in mean corpuscular volume (MCV) at Week 48

Adult TD and NTD Cohorts

Time frame: Baseline, Week 48

Change in mean corpuscular hemoglobin (MCH) at Week 48

Adult TD and NTD Cohorts

Time frame: Baseline, Week 48

Change in nucleated red blood cells (nRBC) at Week 48

Adult TD and NTD Cohorts

Time frame: Baseline, Week 48

Change in red blood cells (RBC) at Week 48

Adult TD and NTD Cohorts

Time frame: Baseline, Week 48

The longest duration with reduction from baseline in the RBC transfusion burden

Adolescent TD Cohort

Time frame: Up to Week 48

The number of participants with ≥ 50% reduction from baseline in RBC transfusion burden during an continuous 12 weeks during Weeks 13-48

Adolescent TD Cohort

Time frame: Up to Week 48

The number of participants with ≥ 33% reduction from baseline in RBC transfusion burden during an continuous 24 weeks

Adolescent TD Cohort

Time frame: Up to Week 48

Number of participants achieving an increase from baseline of ≥1.0g/dL in mean Hb values in absence of transfusions from Week 13 to Week 24

Adolescent NTD Cohort

Time frame: Up to Week 24

Cumulative time (in weeks) with an increase from baseline of ≥1.0g/dL in mean Hb values in absence of RBC transfusions within 48 weeks

Adolescent NTD Cohort

Time frame: Up to Week 48

Number of participants who achieve an increase in mean Hb of >10g/dL values during any continuous 12-week interval during week 13 to week 48 in the absence of transfusions

Adolescent NTD Cohort

Time frame: Up to Week 48

The longest duration with an increase from baseline of ≥1.0g/dL in mean Hb values in absence of transfusions

Adolescent NTD Cohort

Time frame: Up to Week 48

Number of participants with antidrug antibody (ADA)

Adolescent TD and NTD Cohorts

Time frame: Up to Week 48

Mean change in biomarkers for hemolysis

Adolescent TD and NTD Cohorts Biomarkers for hemolysis to be evaluated include total/direct/indirect bilirubin, serum lactate dehydrogenase (sLDH), haptoglobin, reticulocytes and nucleated red blood cells, reticulocyte production index (RPI), and urinary urobilinogen

Time frame: Up to Week 48

Mean change in biomarkers and parameters for iron homeostasis

Adolescent TD and NTD Cohorts The biomarkers and parameters for iron homeostasis to be evaluated include serum ferritin, LIC, myocardial iron concentration (MIC), ICT, myocardial T2(TD participants), and extramedullary hematopoiesis (EMH) mass(es) when present (NTD participants)

Time frame: Up to 1 Year

Hematologic assessments

Adolescent TD and NTD Cohorts The hematologic assessments to be evaluated are red blood cell count, hemoglobin, hematocrit, reticulocyte count, nucleated red blood cell count, platelet count, mean cell volume, mean cell hemoglobin, mean corpuscular hemoglobin concentration, red blood cell distribution width, red blood cell morphology, and globin precipitates

Time frame: Up to Week 48

The change from baseline in the number of health care resource utilization (HCRU)

Adolescent TD and NTD Cohorts

Time frame: Up to Week 48

Mean change from baseline in Pediatric Quality of Life Inventory (PedsQL) domain scores

Adolescent TD and NTD Cohorts

Time frame: Up to Week 48

Mean change from baseline EQ-5D-5L utility index

Adolescent TD and NTD Cohorts

Time frame: Up to Week 48

Mean change from baseline visual analogue scale (VAS) scores

Adolescent TD and NTD Cohorts

Time frame: Up to Week 48