Myelodysplastic Syndromes
Conditions
Brief summary
This study is an open-label extension study for participants previously enrolled in study MK-6143-001 (formerly called A536-03, ClinicalTrials.gov Identifier NCT01749514), to evaluate the long-term safety and tolerability of luspatercept (MK-6143) in participants with low or intermediate-1 risk MDS.
Detailed description
This study is an open-label extension study to evaluate the safety, tolerability, and pharmacodynamic effects of up to 24 months of luspatercept treatment in participants with low or intermediate-1 risk myelodysplastic syndromes previously treated with luspatercept for up to 3 months in MK-6143-001 study (NCT01749514). The starting dose level in this study will be 1.0 mg/kg by subcutaneous (SC) injection every 3 weeks. Dose titration/modification rules will be followed for individual participants and will be based upon safety and efficacy data collected during the course of treatment.
Interventions
DRUGLuspatercept
Luspatercept 1.0 mg/kg once every 3 weeks by subcutaneous injection.
Sponsors
Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Completion of the treatment period in the base study MK-6143-001 (ClinicalTrials.gov Identifier: NCT01749514) * Adequate birth control measures * Patient is able to adhere to the study visit schedule, understand and comply with all protocol requirements * Patient understands and is able to provide written informed consent * In addition, patients with treatment interruption (defined as patients who complete their end-of-study visit in MK-6143-001 and cannot directly roll over to MK-6143-003) must also meet the following criteria: * Documented diagnosis of idiopathic/de novo MDS or non-proliferative chronic myelomonocytic leukemia (CMML) according to the World Health Organization (WHO) criteria 16 (white blood count (WBC) \< 13,000/μL) that meets International Prognostic Scoring System (IPSS) classification of low or intermediate-1 risk disease as determined by microscopic and standard cytogenetic analyses of the bone marrow and peripheral complete blood count (CBC) obtained during screening; * Anemia defined as: * Mean hemoglobin concentration \< 10.0 g/dL of 2 measurements (one performed within one day prior to Cycle 1 Day 1 and the other performed 7-28 days prior to Cycle 1 Day 1), for non-transfusion dependent (NTD) patients (defined as having received ˂ 4 units of red blood cells (RBCs) within 8 weeks prior to Cycle 1 Day 1), OR * Transfusion Dependent (TD), defined as having received ≥ 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1 * Platelet count ≥ 30 x 109/L * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (if related to anemia) * Adequate renal (creatinine ≤ 2.0 x upper limit of normal \[ULN\]) and hepatic (total bilirubin \< 2 x ULN and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 x ULN) function
Exclusion criteria
* Discontinuation/withdrawal from the base study A536-03 (due to patient request, patient unwillingness or inability to comply with the protocol, pregnancy, use of prohibited medication \[e.g. azacitidine\], medical reason or adverse event (AE), hypersensitivity reaction to the study drug, at the discretion of the sponsor, or loss to follow-up) prior to completion of the treatment period * Prior treatment with azacitidine or decitabine * Treatment within 28 days prior to Cycle 1 Day 1 with: * An erythropoiesis-stimulating agent (ESA), * Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF), * Lenalidomide * Iron chelation therapy if initiated within 56 days prior to Cycle 1 Day 1 * Treatment with another investigational drug (including sotatercept \[ACE-011\]) or device, or approved therapy for investigational use ≤ 28 days prior to Cycle 1 Day 1, or if the half-life of the previous investigational product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever is longer * Major surgery within 28 days prior to Cycle 1 Day 1. Patients must have completely recovered from any previous surgery prior to Cycle 1 Day 1 * Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B (HBV) or active infectious hepatitis C (HCV) * Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 150 mm Hg or diastolic blood pressure (DBP) ≥ 100 mm Hg * Pregnant or lactating females * History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug * Any other condition not specifically noted above which, in the judgment of the investigator, would preclude the patient from participating in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 5 years | An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The number of participants who experienced an AE was reported. |
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to approximately 5 years | An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The number of participants who discontinued luspatercept due to an AE was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Neutrophil Response (HI-N) Per IWG 2006 Response Criteria | Any consecutive 8 Weeks during the study (up to approximately 5 years) | Per IWG 2006 response criteria, HI-N response was defined for participants with baseline absolute neutrophil count (ANC) \<1.0×10\^9/L as the percentage increase ≥100% and an absolute mean increase \>0.5 ×10\^9/L during any rolling 8-week window on treatment compared with baseline. The rolling 8-week was defined as any consecutive 8 weeks during the study. Percentage of participants with HI-N response were reported. |
| Rate of Platelet Response (HI-P) Per IWG 2006 Response Criteria | Any consecutive 8 Weeks during the study (up to approximately 5 years) | Per IWG 2006 response criteria, HI-P response was defined for participants with baseline platelet count \<100×10\^9/L as the following: 1) For participants with baseline ≥20×10\^9/L, an absolute increase of ≥30×10\^9/L during any rolling 8-week window on treatment and 2) For participants with baseline \<20×10\^9/L, mean value of \>20×10\^9/L and percentage increase ≥100% during any rolling 8-week window on treatment. The rolling 8-week was defined as any consecutive 8 weeks during the study. Percentage of participants with HI-P response were reported. |
| Duration of HI-E in LTB Participants Per IWG 2006 Response Criteria | up to approximately 5 years | For LTB participants, HI-E was defined as all Hgb increase ≥1.5 g/dL during any rolling 8 weeks window. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. Per IWG 2006 response criteria, duration of HI-E was defined as the time from the first day of the first rolling 8 weeks interval of showing response to the last day of the last consecutive rolling 8 weeks interval of showing response. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. When there were multiple disjointed intervals with response, the longest interval was used. |
| Duration of HI-E in HTB Participants Per IWG 2006 Response Criteria | up to approximately 5 years | For HTB participants, HI-E was defined as RBC transfusion reduction ≥4 units during any rolling 8 weeks. HTB participants were those who required a transfusion of ≥4 units of RBCs in the 8 weeks prior to baseline. Per IWG 2006 response criteria, duration of HI-E was defined as the time from the first day of the first rolling 8 weeks interval of showing response to the last day of the last consecutive rolling 8 weeks interval of showing response. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. When there were multiple disjointed intervals with response, the longest interval was used. |
| Time to HI-E in LTB Participants Per IWG 2006 Response Criteria | up to approximately 5 years | For LTB participants, HI-E was defined as all Hgb increase ≥1.5 g/dL during any rolling 8 weeks window. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. Per IWG 2006 response criteria, time to HI-E was defined as the first date of the rolling 8 weeks interval of showing response minus first dose date plus 1. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. When there were multiple disjointed intervals with response, the longest interval was used. |
| Time to HI-E in HTB Participants Per IWG 2006 Response Criteria | Any consecutive 8 weeks during the study (up to approximately 5 years) | For HTB participants, HI-E was defined as RBC transfusion reduction ≥4 units during any rolling 8 weeks. HTB participants were those who required a transfusion of ≥4 units of RBCs in the 8 weeks prior to baseline. Per IWG 2006 response criteria, time to HI-E was defined as the first date of the rolling 8 weeks interval of showing response minus first dose date plus 1. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. |
| Rate of RBC Transfusion Independence (RBC-TI) | Any consecutive 8 Weeks during the study (up to approximately 5 years) | Per protocol, RBC-TI response was defined as not requiring RBC transfusion for 8 or more weeks while on treatment among participants with ≥2 units of RBC transfusions at baseline. The rate of RBC-TI was defined as the percentage of participants with ≥2 units of RBC transfusions at baseline with RBC-TI. |
| Mean Change From Baseline to Week 8 in RBC Transfusion Burden (TB) in HTB Participants | Baseline and up to 5 years | RBC TB was defined as ≥4 units or 50% reduction during rolling 8 weeks among HTB participants. The rolling 8-week was defined as any consecutive 8 weeks during the study. HTB participants are those who required a transfusion of ≥4 units of RBCs in the 8 weeks prior to baseline. Mean change from baseline to Week 8 in reduction in RBC TD in HTB participants was reported. |
| Mean Change From Baseline to Week 8 in Hemoglobin Levels ≥1.5 Grams/dL in LTB Participants | Baseline and Week 8 | Baseline hemoglobin levels were the documented pre-transfusion hemoglobin values during the 12 weeks prior to treatment. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. Mean change from baseline to Week 8 in hemoglobin levels ≥1.5 grams/dL in LTB participants were reported. |
| Serum Concentration of Luspatercept | Day 1: Cycles 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, and 81 (each cycle length = 21 days); End of treatment (EOT) Day 1853 | Blood samples were collected at pre-determined time points to determine the serum concentration of luspatercept. Serum concentrations that were below the limit of quantitation (LOQ) of the assay prior to the first dose were assigned a numerical value of zero. Post-treatment serum concentrations that were below the LOQ of the assay were treated as missing. Serum concentrations assigned a value of missing were omitted from the analysis. The LOQ of the assay was 50 ng/mL. |
| Percent Change From Baseline to Day 1853 in Concentration of Serum Iron | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were collected at pre-specified time intervals to determine serum iron concentration. The percentage change from baseline to Day 1853 in concentration of serum iron was reported. |
| Percent Change From Baseline to Day 1853 in Total Iron Binding Capacity (TIBC) | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were collected at pre-specified time intervals to determine TIBC. The percentage change from baseline to Day 1853 in TIBC was reported. |
| Percentage of Participants With Modified Erythroid Response (mHI-E) Per International Working Group (IWG) 2006 Response Criteria | Any consecutive 8 weeks during the study (up to approximately 5 years) | The mHI-E was defined as a mean hemoglobin (Hgb) increase ≥1.5 g/dL over an 8-week period as compared to baseline, not influenced by red blood cell (RBC) transfusion in low transfusion burden (LTB) participants and a decrease of ≥4 units or ≥50% of units of RBCs transfused over a period of 8 weeks, relative to the number of units of RBCs transfused in the 8 weeks immediately prior to baseline in high transfusion burden (HTB) participants. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. HTB participants were those who required a transfusion of ≥4 units of RBCs in the 8 weeks prior to baseline. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. |
| Percent Change From Baseline to Day 1853 in Concentration of Soluble Transferrin Receptor | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were collected at pre-specified time intervals to determine soluble transferrin receptor concentration. The percentage change from baseline to Day 1853 in concentration of soluble transferrin receptor was reported. |
| Percent Change From Baseline to Day 1853 in Concentration of Serum Ferritin | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were collected at pre-specified time intervals to determine serum ferritin concentration. The percentage change from baseline to Day 1853 in concentration of serum ferritin was reported. |
| Percent Change From Baseline to Day 1853 in Concentration of Non-Transferrin Bound Iron (NTBI) | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were to be collected at pre-specified time intervals to determine concentration of NTBI. Baseline was prespecified to be the last measurement prior to the first dose of study drug. |
| Percent Change From Baseline to Day 1853 in Concentration of Serum Hepcidin | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were to be collected at pre-specified time intervals to determine concentration of serum hepcidin. Baseline was prespecified to be the last measurement prior to the first dose of study drug. |
| Percent Change From Baseline to Day 1853 in Concentration of Serum Erythropoietin | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were collected at pre-specified time intervals to determine serum erythropoietin concentration. The percentage change from baseline to Day 1853 in concentration of serum erythropoietin was reported. |
| Percent Change From Baseline to Day 1853 in Reticulocyte Count | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were collected at pre-specified time intervals to determine reticulocyte count. The percentage change from baseline to Day 1853 in reticulocyte count was reported. |
| Percent Change From Baseline to Day 1853 in Nucleated RBC (nRBC) Count | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were to be collected at pre-specified time intervals to determine nRBC. Baseline was prespecified to be the last measurement prior to the first dose of study drug. |
| Percent Change From Baseline to Day 1853 in Direct Bilirubin Level | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were collected at pre-specified time intervals to determine serum direct bilirubin concentration. The percentage change from baseline to Day 1853 in concentration of direct bilirubin was reported. |
| Percent Change From Baseline to Day 1853 in Total Bilirubin Level | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were collected at pre-specified time intervals to determine total bilirubin concentration. The percentage change from baseline to Day 1853 in concentration of total bilirubin was reported. |
| Percent Change From Baseline to Day 1853 in Lactate Dehydrogenase Level | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were collected at pre-specified time intervals to determine serum lactate dehydrogenase level. The percentage change from baseline to Day 1853 in concentration of lactate dehydrogenase level was reported. |
| Percent Change From Baseline to Day 1853 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP) | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were to be collected at pre-specified time intervals to determine BSAP. Baseline was prespecified to be the last measurement prior to the first dose of study drug. |
| Percent Change From Baseline to Day 1853 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX) | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were to be collected at pre-specified time intervals to determine CTX. Baseline was prespecified to be the last measurement prior to the first dose of study drug. |
| Percent Change From Baseline to Day 1853 in Concentration of Transferrin | Baseline (prior to first dose of luspatercept) and Day 1853 | Blood samples were collected at pre-specified time intervals to determine serum transferrin concentration. The percentage change from baseline to Day 1853 in concentration of transferrin was reported. |
| Rate of Erythroid Response (HI-E) Per IWG 2006 Response Criteria | Any consecutive 8 weeks during the study (up to approximately 5 years) | Per IWG 2006 response criteria, the rate of HI-E was defined as the percentage of participants with an HI-E response by an Hgb increase of ≥1.5 g/dL for participants not transfused or as defined by having received less than 4 units of RBCs within 8 weeks of baseline or reduction by ≥4 units of RBCs transfused (for a Hgb≤9.0 g/dL) during any 8-week period on study, compared with the 8-week period prior to study day 1. |
Countries
Germany
Participant flow
Pre-assignment details
This extension study enrolled participants from base study MK-6143-001 (NCT01749514). Participants were referred as 'Direct Roll Over' participants (n=67; enrolled within \ 28 days after last dose of luspatercept and did not complete post treatment follow up (PTFU) or end of study (EOS) visit of base study) or 'Treatment Interrupted' participants (n=8; completed EOS visit for base study). Per protocol, a total of 75 participants were pooled together in the extension study.
Participants by arm
| Arm | Count |
|---|---|
| Luspatercept Extension Population Participants received luspatercept dose of either 0.5, 0.75, 1.0, 1.33, or 1.75 mg/kg determined via Fibonacci scheme on Day 1 of each 21-day cycle for up to 87 cycles (up to approximately 5 years) as a subcutaneous (SC) injection. Direct Roll Over participants received the highest tolerated dose of luspatercept that was assigned in the base study. Treatment Interrupted participants received an initial dose of luspatercept 1mg/kg on Day 1 of Cycle 1 (cycle length = 21 days) and the subsequent doses were titrated up to 1.75mg/kg Q3W via Fibonacci scheme, on Day 1 of each cycle for up to 87 cycles (for up to approximately 5 years). | 75 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 12 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Not reported | 12 |
| Overall Study | Presence of ≥1% blasts in peripheral blood | 1 |
| Overall Study | Protocol deviation | 3 |
| Overall Study | Sponsor decision | 22 |
| Overall Study | Withdrawal by Subject | 9 |
Baseline characteristics
| Characteristic | Luspatercept Extension Population |
|---|---|
| Age, Continuous | 70.9 Years STANDARD_DEVIATION 11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Hemoglobin level | 8.74 grams/dl STANDARD_DEVIATION 1.01 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 75 Participants |
| Sex: Female, Male Female | 25 Participants |
| Sex: Female, Male Male | 50 Participants |
| Transfusion Status HTB | 25 Participants |
| Transfusion Status LTB | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 2 | 4 / 73 | 3 / 61 | 6 / 49 |
| other Total, other adverse events | 0 / 1 | 1 / 2 | 44 / 73 | 29 / 61 | 38 / 49 |
| serious Total, serious adverse events | 1 / 1 | 1 / 2 | 19 / 73 | 16 / 61 | 34 / 49 |
Outcome results
Primary
Number of Participants Who Discontinued Study Treatment Due to an AE
An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The number of participants who discontinued luspatercept due to an AE was reported.
Time frame: Up to approximately 5 years
Population: All enrolled participants who received at least one dose of luspatercept.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Luspatercept Extension Population | Number of Participants Who Discontinued Study Treatment Due to an AE | 23 Participants |
Primary
Number of Participants Who Experienced an Adverse Event (AE)
An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The number of participants who experienced an AE was reported.
Time frame: Up to approximately 5 years
Population: All enrolled participants who received at least one dose of luspatercept.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Luspatercept Extension Population | Number of Participants Who Experienced an Adverse Event (AE) | 75 Participants |
Secondary
Duration of HI-E in HTB Participants Per IWG 2006 Response Criteria
For HTB participants, HI-E was defined as RBC transfusion reduction ≥4 units during any rolling 8 weeks. HTB participants were those who required a transfusion of ≥4 units of RBCs in the 8 weeks prior to baseline. Per IWG 2006 response criteria, duration of HI-E was defined as the time from the first day of the first rolling 8 weeks interval of showing response to the last day of the last consecutive rolling 8 weeks interval of showing response. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. When there were multiple disjointed intervals with response, the longest interval was used.
Time frame: up to approximately 5 years
Population: All enrolled HTB participants who received at lease one dose of luspatercept and had a HI-E.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Duration of HI-E in HTB Participants Per IWG 2006 Response Criteria | 328 Days | Standard Deviation 286.8 |
Secondary
Duration of HI-E in LTB Participants Per IWG 2006 Response Criteria
For LTB participants, HI-E was defined as all Hgb increase ≥1.5 g/dL during any rolling 8 weeks window. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. Per IWG 2006 response criteria, duration of HI-E was defined as the time from the first day of the first rolling 8 weeks interval of showing response to the last day of the last consecutive rolling 8 weeks interval of showing response. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. When there were multiple disjointed intervals with response, the longest interval was used.
Time frame: up to approximately 5 years
Population: All enrolled LTB participants who received at least one dose of luspatercept and had a HI-E.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Duration of HI-E in LTB Participants Per IWG 2006 Response Criteria | 299 Days | Standard Deviation 378.3 |
Secondary
Mean Change From Baseline to Week 8 in Hemoglobin Levels ≥1.5 Grams/dL in LTB Participants
Baseline hemoglobin levels were the documented pre-transfusion hemoglobin values during the 12 weeks prior to treatment. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. Mean change from baseline to Week 8 in hemoglobin levels ≥1.5 grams/dL in LTB participants were reported.
Time frame: Baseline and Week 8
Population: All enrolled LTB participants who received at least one dose of luspatercept.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Mean Change From Baseline to Week 8 in Hemoglobin Levels ≥1.5 Grams/dL in LTB Participants | 2.4 grams/dl | Standard Deviation 1 |
Secondary
Mean Change From Baseline to Week 8 in RBC Transfusion Burden (TB) in HTB Participants
RBC TB was defined as ≥4 units or 50% reduction during rolling 8 weeks among HTB participants. The rolling 8-week was defined as any consecutive 8 weeks during the study. HTB participants are those who required a transfusion of ≥4 units of RBCs in the 8 weeks prior to baseline. Mean change from baseline to Week 8 in reduction in RBC TD in HTB participants was reported.
Time frame: Baseline and up to 5 years
Population: All enrolled HTB participants who received at least one dose of luspatercept.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Mean Change From Baseline to Week 8 in RBC Transfusion Burden (TB) in HTB Participants | -4.4 Units of blood | Standard Deviation 2.6 |
Secondary
Percentage of Participants With Modified Erythroid Response (mHI-E) Per International Working Group (IWG) 2006 Response Criteria
The mHI-E was defined as a mean hemoglobin (Hgb) increase ≥1.5 g/dL over an 8-week period as compared to baseline, not influenced by red blood cell (RBC) transfusion in low transfusion burden (LTB) participants and a decrease of ≥4 units or ≥50% of units of RBCs transfused over a period of 8 weeks, relative to the number of units of RBCs transfused in the 8 weeks immediately prior to baseline in high transfusion burden (HTB) participants. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. HTB participants were those who required a transfusion of ≥4 units of RBCs in the 8 weeks prior to baseline. Rolling 8 weeks was defined as any consecutive 8 weeks during the study.
Time frame: Any consecutive 8 weeks during the study (up to approximately 5 years)
Population: All enrolled participants who received at least one dose of luspatercept and were mHI-E evaluable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept Extension Population | Percentage of Participants With Modified Erythroid Response (mHI-E) Per International Working Group (IWG) 2006 Response Criteria | 81.3 Percentage of participants |
Secondary
Percent Change From Baseline to Day 1853 in Concentration of Non-Transferrin Bound Iron (NTBI)
Blood samples were to be collected at pre-specified time intervals to determine concentration of NTBI. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: No data were collected for the percent change from baseline to day 1853 in concentration of NTBI.
Secondary
Percent Change From Baseline to Day 1853 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP)
Blood samples were to be collected at pre-specified time intervals to determine BSAP. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: No data were collected for the percent change from baseline to day 1853 in concentration of BSAP.
Secondary
Percent Change From Baseline to Day 1853 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX)
Blood samples were to be collected at pre-specified time intervals to determine CTX. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: No data were collected for the percent change from baseline to day 1853 in concentration of CTX.
Secondary
Percent Change From Baseline to Day 1853 in Concentration of Serum Erythropoietin
Blood samples were collected at pre-specified time intervals to determine serum erythropoietin concentration. The percentage change from baseline to Day 1853 in concentration of serum erythropoietin was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: All enrolled participants who received at least one dose of luspatercept and had data available for erythropoietin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Percent Change From Baseline to Day 1853 in Concentration of Serum Erythropoietin | 2252.15 Percent change | Standard Deviation 14490.3 |
Secondary
Percent Change From Baseline to Day 1853 in Concentration of Serum Ferritin
Blood samples were collected at pre-specified time intervals to determine serum ferritin concentration. The percentage change from baseline to Day 1853 in concentration of serum ferritin was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: All enrolled participants who received at least one dose of luspatercept and had data available for serum ferritin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Percent Change From Baseline to Day 1853 in Concentration of Serum Ferritin | 71.61 Percent change | Standard Deviation 152.948 |
Secondary
Percent Change From Baseline to Day 1853 in Concentration of Serum Hepcidin
Blood samples were to be collected at pre-specified time intervals to determine concentration of serum hepcidin. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: No data were collected for the percent change from baseline to day 1853 in concentration of serum hepcidin.
Secondary
Percent Change From Baseline to Day 1853 in Concentration of Serum Iron
Blood samples were collected at pre-specified time intervals to determine serum iron concentration. The percentage change from baseline to Day 1853 in concentration of serum iron was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: All enrolled participants who received at least one dose of luspatercept and had data available for serum iron.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Percent Change From Baseline to Day 1853 in Concentration of Serum Iron | 20.38 Percent change | Standard Deviation 70.489 |
Secondary
Percent Change From Baseline to Day 1853 in Concentration of Soluble Transferrin Receptor
Blood samples were collected at pre-specified time intervals to determine soluble transferrin receptor concentration. The percentage change from baseline to Day 1853 in concentration of soluble transferrin receptor was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: All enrolled participants who received at least one dose of luspatercept and had data available for soluble transferrin receptor.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Percent Change From Baseline to Day 1853 in Concentration of Soluble Transferrin Receptor | 11.52 Percent change | Standard Deviation 48.541 |
Secondary
Percent Change From Baseline to Day 1853 in Concentration of Transferrin
Blood samples were collected at pre-specified time intervals to determine serum transferrin concentration. The percentage change from baseline to Day 1853 in concentration of transferrin was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: All enrolled participants who received at least one dose of luspatercept and had data available for transferrin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Percent Change From Baseline to Day 1853 in Concentration of Transferrin | -11.34 Percent change | Standard Deviation 11.587 |
Secondary
Percent Change From Baseline to Day 1853 in Direct Bilirubin Level
Blood samples were collected at pre-specified time intervals to determine serum direct bilirubin concentration. The percentage change from baseline to Day 1853 in concentration of direct bilirubin was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: All enrolled participants who received at least one dose of luspatercept and had data available for direct bilirubin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Percent Change From Baseline to Day 1853 in Direct Bilirubin Level | 110.53 Percent change | Standard Deviation 572.494 |
Secondary
Percent Change From Baseline to Day 1853 in Lactate Dehydrogenase Level
Blood samples were collected at pre-specified time intervals to determine serum lactate dehydrogenase level. The percentage change from baseline to Day 1853 in concentration of lactate dehydrogenase level was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: All enrolled participants who received at least one dose of luspatercept and had data available for lactate dehydrogenase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Percent Change From Baseline to Day 1853 in Lactate Dehydrogenase Level | 22.98 Percent change | Standard Deviation 43.017 |
Secondary
Percent Change From Baseline to Day 1853 in Nucleated RBC (nRBC) Count
Blood samples were to be collected at pre-specified time intervals to determine nRBC. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: No data were collected for the percent change from baseline to day 1853 in nRBC count.
Secondary
Percent Change From Baseline to Day 1853 in Reticulocyte Count
Blood samples were collected at pre-specified time intervals to determine reticulocyte count. The percentage change from baseline to Day 1853 in reticulocyte count was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: All enrolled participants who received at least one dose of luspatercept and had data available for reticulocyte.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Percent Change From Baseline to Day 1853 in Reticulocyte Count | 78.70 Percent change | Standard Deviation 137.168 |
Secondary
Percent Change From Baseline to Day 1853 in Total Bilirubin Level
Blood samples were collected at pre-specified time intervals to determine total bilirubin concentration. The percentage change from baseline to Day 1853 in concentration of total bilirubin was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: All enrolled participants who received at least one dose of luspatercept and had data available for total bilirubin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Percent Change From Baseline to Day 1853 in Total Bilirubin Level | 72.17 Percent change | Standard Deviation 236.953 |
Secondary
Percent Change From Baseline to Day 1853 in Total Iron Binding Capacity (TIBC)
Blood samples were collected at pre-specified time intervals to determine TIBC. The percentage change from baseline to Day 1853 in TIBC was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 1853
Population: All enrolled participants who received at least one dose of luspatercept and had data available for TIBC.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Percent Change From Baseline to Day 1853 in Total Iron Binding Capacity (TIBC) | -11.37 Percent change | Standard Deviation 11.979 |
Secondary
Rate of Erythroid Response (HI-E) Per IWG 2006 Response Criteria
Per IWG 2006 response criteria, the rate of HI-E was defined as the percentage of participants with an HI-E response by an Hgb increase of ≥1.5 g/dL for participants not transfused or as defined by having received less than 4 units of RBCs within 8 weeks of baseline or reduction by ≥4 units of RBCs transfused (for a Hgb≤9.0 g/dL) during any 8-week period on study, compared with the 8-week period prior to study day 1.
Time frame: Any consecutive 8 weeks during the study (up to approximately 5 years)
Population: All enrolled participants who received at least one dose of luspatercept and were HI-E evaluable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept Extension Population | Rate of Erythroid Response (HI-E) Per IWG 2006 Response Criteria | 80.0 Percentage of participants |
Secondary
Rate of Neutrophil Response (HI-N) Per IWG 2006 Response Criteria
Per IWG 2006 response criteria, HI-N response was defined for participants with baseline absolute neutrophil count (ANC) \<1.0×10\^9/L as the percentage increase ≥100% and an absolute mean increase \>0.5 ×10\^9/L during any rolling 8-week window on treatment compared with baseline. The rolling 8-week was defined as any consecutive 8 weeks during the study. Percentage of participants with HI-N response were reported.
Time frame: Any consecutive 8 Weeks during the study (up to approximately 5 years)
Population: All enrolled participants who received at least one dose of luspatercept and had baseline neutrophil count \<1.0×10\^9/L.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept Extension Population | Rate of Neutrophil Response (HI-N) Per IWG 2006 Response Criteria | 64.3 Percentage of participants |
Secondary
Rate of Platelet Response (HI-P) Per IWG 2006 Response Criteria
Per IWG 2006 response criteria, HI-P response was defined for participants with baseline platelet count \<100×10\^9/L as the following: 1) For participants with baseline ≥20×10\^9/L, an absolute increase of ≥30×10\^9/L during any rolling 8-week window on treatment and 2) For participants with baseline \<20×10\^9/L, mean value of \>20×10\^9/L and percentage increase ≥100% during any rolling 8-week window on treatment. The rolling 8-week was defined as any consecutive 8 weeks during the study. Percentage of participants with HI-P response were reported.
Time frame: Any consecutive 8 Weeks during the study (up to approximately 5 years)
Population: All enrolled participants who received at least one dose of luspatercept and had baseline platelet \<100x10\^9/L.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept Extension Population | Rate of Platelet Response (HI-P) Per IWG 2006 Response Criteria | 36.4 Percentage of participants |
Secondary
Rate of RBC Transfusion Independence (RBC-TI)
Per protocol, RBC-TI response was defined as not requiring RBC transfusion for 8 or more weeks while on treatment among participants with ≥2 units of RBC transfusions at baseline. The rate of RBC-TI was defined as the percentage of participants with ≥2 units of RBC transfusions at baseline with RBC-TI.
Time frame: Any consecutive 8 Weeks during the study (up to approximately 5 years)
Population: All enrolled participants who received at least one dose of luspatercept and had ≥2 units of RBC transfusions at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept Extension Population | Rate of RBC Transfusion Independence (RBC-TI) | 64.3 Percentage of participants |
Secondary
Serum Concentration of Luspatercept
Blood samples were collected at pre-determined time points to determine the serum concentration of luspatercept. Serum concentrations that were below the limit of quantitation (LOQ) of the assay prior to the first dose were assigned a numerical value of zero. Post-treatment serum concentrations that were below the LOQ of the assay were treated as missing. Serum concentrations assigned a value of missing were omitted from the analysis. The LOQ of the assay was 50 ng/mL.
Time frame: Day 1: Cycles 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, and 81 (each cycle length = 21 days); End of treatment (EOT) Day 1853
Population: All participants who received at least one dose of luspatercept and had data available for serum concentration analysis available at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 25 Day 1 | 7.986 µg/mL | Standard Deviation 4.061 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 1 Day 1 | 0.509 µg/mL | Standard Deviation 0.738 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 5 Day 1 | 6.373 µg/mL | Standard Deviation 3.527 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 9 Day 1 | 6.589 µg/mL | Standard Deviation 4.32 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 13 Day 1 | 7.154 µg/mL | Standard Deviation 4.423 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 17 Day 1 | 8.136 µg/mL | Standard Deviation 4.476 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 21 Day 1 | 8.227 µg/mL | Standard Deviation 3.811 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 29 Day 1 | 8.379 µg/mL | Standard Deviation 2.884 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 33 Day 1 | 8.024 µg/mL | Standard Deviation 3.035 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 37 Day 1 | 8.017 µg/mL | Standard Deviation 3.724 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 41 Day 1 | 7.559 µg/mL | Standard Deviation 3.582 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 45 Day 1 | 8.614 µg/mL | Standard Deviation 4.015 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 49 Day 1 | 9.447 µg/mL | Standard Deviation 2.967 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 53 Day 1 | 7.936 µg/mL | Standard Deviation 2.982 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 57 Day 1 | 8.891 µg/mL | Standard Deviation 3.053 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 61 Day 1 | 8.288 µg/mL | Standard Deviation 3.753 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 65 Day 1 | 8.698 µg/mL | Standard Deviation 4.729 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 69 Day 1 | 7.603 µg/mL | Standard Deviation 3.144 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 73 Day 1 | 8.559 µg/mL | Standard Deviation 3.68 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 77 Day 1 | 7.539 µg/mL | Standard Deviation 2.555 |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | Cycle 81 Day 1 | 9.837 µg/mL | — |
| Luspatercept Extension Population | Serum Concentration of Luspatercept | EOT (Day 1853) | 6.732 µg/mL | Standard Deviation 4.356 |
Secondary
Time to HI-E in HTB Participants Per IWG 2006 Response Criteria
For HTB participants, HI-E was defined as RBC transfusion reduction ≥4 units during any rolling 8 weeks. HTB participants were those who required a transfusion of ≥4 units of RBCs in the 8 weeks prior to baseline. Per IWG 2006 response criteria, time to HI-E was defined as the first date of the rolling 8 weeks interval of showing response minus first dose date plus 1. Rolling 8 weeks was defined as any consecutive 8 weeks during the study.
Time frame: Any consecutive 8 weeks during the study (up to approximately 5 years)
Population: All enrolled HTB participants who received at lease one dose of luspatercept and had a HI-E.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Time to HI-E in HTB Participants Per IWG 2006 Response Criteria | 13 Days | Standard Deviation 22.6 |
Secondary
Time to HI-E in LTB Participants Per IWG 2006 Response Criteria
For LTB participants, HI-E was defined as all Hgb increase ≥1.5 g/dL during any rolling 8 weeks window. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. Per IWG 2006 response criteria, time to HI-E was defined as the first date of the rolling 8 weeks interval of showing response minus first dose date plus 1. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. When there were multiple disjointed intervals with response, the longest interval was used.
Time frame: up to approximately 5 years
Population: All enrolled LTB participants who received at least one dose of luspatercept and had a HI-E.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept Extension Population | Time to HI-E in LTB Participants Per IWG 2006 Response Criteria | 83 Days | Standard Deviation 86.2 |