Anemia
Conditions
Keywords
Luspatercept, BMS-986346, ACE-536, α-thalassemia, Alpha Thalassemia, Reblozyl, Transfusions, Non-transfusion dependent, RBC transfusion dependent
Brief summary
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.
Interventions
BIOLOGICALLuspatercept
Specified dose on specified days
DRUGPlacebo
Specified dose on specified days
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult participant≥ 18 years with documented diagnosis of A-Thal HbH disease with Transfusion dependence defined as:. i) TD participant: ≥ 6 RBC units during the 24 weeks prior to randomization. ii) 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:. i) 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. ii) 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. iii) Participant has Karnofsky (age ≥16 years) or Lansky (age \< 16 years) performance status score ≥ 50 at screening.
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. Applicable for the EU only: Bleeding disorders manifested by frequent bleeding episodes (eg, menorrhagia, epistaxis, clotting disorders). * 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to Week 48 | Adult TD Cohort |
| 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 | Up to Week 24 | Adult NTD Cohort |
| 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 | Up to Week 3 | Adolescent TD and NTD Cohorts |
| Number of participants with adverse events (AEs) | Up to 5 years | Adolescent TD and NTD Cohorts |
| Pharmacokinetics (PK): Serum concentration of Luspatercept | Up to Week 108 | Adolescent TD and NTD Cohorts |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to Week 108 | Adult TD Cohort |
| The longest duration with ≥ 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units | Up to Week 108 | Adult TD Cohort |
| Number of RBC transfusion units from week 1 to week 48 | Up to Week 48 | Adult and Adolescent TD Cohorts |
| Change from baseline in hemoglobin in the absence of transfusion at Week 24 | Up to Week 24 | Adult and Adolescent NTD Cohorts |
| 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 | Up to Week 108 | Adult NTD Cohort |
| Time Duration with an increase from baseline of ≥ 1.0 g/dL in hemoglobin values in the absence of transfusion within 48 weeks | Up to Week 48 | Adult NTD Cohort |
| 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 | Up to Week 24 | Adult NTD Cohort |
| ≥ 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 | Up to Week 24 | Adult NTD Cohort |
| Number of participants with AEs | Up to 5 years | Adult and Adolescent TD and NTD Cohorts |
| Number of participants with laboratory abnormalities | Up to 5 Years | Adult TD and NTD Cohorts |
| Number of participants with immunogenicity | Up to 2 Years | Adult TD and NTD Cohorts |
| 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 | Up to Week 48 | Adult TD Cohort |
| 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 | Up to Week 108 | Adult TD Cohort |
| 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 | Up to Week 48 | Adult TD Cohort |
| 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 | Up to Week 48 | Adult TD Cohort |
| 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 | Up to Week 48 | Adult TD Cohort |
| 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 | Up to Week 48 | Adult TD Cohort |
| 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 | Up to Week 48 | Adult TD Cohort |
| The longest duration of RBC transfusion-free period for participants who achieve transfusion-free period of ≥ 12 weeks | Up to Week 108 | Adult TD Cohort |
| 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) | Up to Week 108 | Adult TD Cohort |
| Time from first dose to first day of response (rolling 12-week and 24-week response, both for ≥ 33% and ≥ 50% reduction) | Up to Week 108 | Adult TD Cohort |
| Change from baseline in number of transfusion events at Week 48 | Up to Week 48 | Adult TD Cohort |
| Number of participants who achieve RBC transfusion-free period of any continuous ≥ 12 weeks during treatment | Up to Week 108 | Adult and Adolescent TD and NTD Cohorts |
| Number of participants who achieve RBC transfusion-free period of any continuous ≥ 24 weeks during treatment | Up to Week 108 | Adult and Adolescent TD and NTD Cohorts |
| Time to first transfusion | Up to Week 108 | Adult and Adolescent NTD Cohorts |
| Number of transfusions | Within 48 Weeks | Adult NTD Cohort |
| Number of transfusion visits/units | Within 48 Weeks | Adult NTD Cohort |
| 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 | Up to Week 48 | Adult TD and NTD Cohorts |
| 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 | Up to Week 48 | Adult NTD Cohort |
| Time from first to last Hb measurement with increase from baseline by ≥ 1.0 g/dL | Up to Week 108 | Adult NTD Cohorts |
| Time to the first increase from baseline of ≥ 1.0 g/dL in mean Hb value | Up to Week 48 | Adolescent NTD Cohort |
| 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 | Up to Week 48 | Adult NTD Cohort |
| 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 | Up to Week 48 | Adult TD and NTD Cohorts |
| 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 | Up to Week 48 | Adult NTD Cohort |
| Change from baseline in FACT-An FS Score at Week 24 and Week 48 | Up to Week 48 | Adult NTD Cohort |
| Change from baseline in Functional Assessment of Cancer Therapy Anemia Anemia Subscale (FACT-An AS) at Week 24 and Week 48 | Up to Week 48 | Adult NTD Cohort |
| Number of participants with at least one hemolytic crisis | Up to Week 108 | Adult TD and NTD Cohorts |
| Rate of hemolytic crises | Up to Week 108 | Adult TD and NTD Cohorts |
| Time to first hemolytic crisis | Up to Week 108 | Adult TD and NTD Cohorts |
| Time to second hemolytic crisis | Up to Week 108 | Adult TD and NTD Cohorts |
| Change from baseline in hemolysis markers at Week 24 and Week 48 | Up to Week 48 | Adult TD and NTD Cohorts: |
| Change from baseline in the 6-minute walk test (6MWT) distance at Week 24 and Week 48 | Up to Week 48 | Adult NTD Cohort |
| Pharmacokinetics (PK): Serum concentration of Luspatercept | Up to Week 108 | Adult and Adolescent TD and NTD Cohorts |
| Percent Change from Baseline in Biomarkers for Erythropoiesis at Week 48 | Baseline, Week 48 | Adult and Adolescent TD and NTD Cohorts. The biomarkers for erythropoiesis to be evaluated include 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. |
| Percent Change from Baseline in Biomarkers and Parameters for Iron Homeostasis at Week 48 | Up to 5 Years | 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. |
| Percent Change from Baseline in HB Variants including HBH | Baseline, Week 48 | Adult TD and NTD Cohorts. |
| Change in mean corpuscular volume (MCV) at Week 48 | Baseline, Week 48 | Adult TD and NTD Cohorts |
| Change in mean corpuscular hemoglobin (MCH) at Week 48 | Baseline, Week 48 | Adult TD and NTD Cohorts |
| Change in nucleated red blood cells (nRBC) at Week 48 | Baseline, Week 48 | Adult TD and NTD Cohorts |
| Change in red blood cells (RBC) at Week 48 | Baseline, Week 48 | Adult TD and NTD Cohorts |
| The longest duration with reduction from baseline in the RBC transfusion burden | Up to Week 48 | Adolescent TD Cohort |
| The number of participants with ≥ 50% reduction from baseline in RBC transfusion burden during an continuous 12 weeks during Weeks 13-48 | Up to Week 48 | Adolescent TD Cohort |
| The number of participants with ≥ 33% reduction from baseline in RBC transfusion burden during an continuous 24 weeks | Up to Week 48 | Adolescent TD Cohort |
| 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 | Up to Week 24 | Adolescent NTD Cohort |
| 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 | Up to Week 48 | Adolescent NTD Cohort |
| 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 | Up to Week 48 | Adolescent NTD Cohort |
| The longest duration with an increase from baseline of ≥1.0g/dL in mean Hb values in absence of transfusions | Up to Week 48 | Adolescent NTD Cohort |
| Number of participants with antidrug antibody (ADA) | Up to 2 Years | Adolescent TD and NTD Cohorts |
| Mean change in biomarkers for hemolysis | Up to Week 48 | 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 |
| Mean change in biomarkers and parameters for iron homeostasis | Up to 5 Years | Adolescent TD and NTD Cohorts. The biomarkers and parameters for iron homeostasis to be evaluated include serum ferritin, liver and myocardial iron content (LIC), (MIC), iron chelation therapy (ICT). |
| Assessment of Hematologic Parameters | Up to Week 48 | Adolescent TD and NTD Cohorts. The hematologic assessments to be evaluated are red blood cell (RBC) count, hemoglobin, hematocrit, reticulocyte count, nucleated red blood cell count, platelet, leukocyte and neutrophile counts, RBC indices, RBC morphology, and Hb variants. |
| The change from baseline in the number of health care resource utilization (HCRU) | Up to 5 Years | Adolescent TD and NTD Cohorts |
| Mean change from baseline in Pediatric Quality of Life Inventory (PedsQL) domain scores | Up to 3 Years | Adolescent TD and NTD Cohorts |
| Mean change from baseline EQ-5D-5L utility index | Up to 3 Years | Adolescent TD and NTD Cohorts |
| Mean change from baseline visual analogue scale (VAS) scores | Up to 3 Years | Adolescent TD and NTD Cohorts |
Countries
China, Greece, Hong Kong, Italy, Malaysia, Saudi Arabia, Singapore, Taiwan, Thailand, Turkey (Türkiye)
Contacts
STUDY_DIRECTORBristol-Myers Squibb
Bristol-Myers Squibb
Outcome results
None listed