Clinical trial NCT02268409: Extension Study to Evaluate the Safety and Efficacy of Luspatercept in Participants With β-Thalassemia Previously Enrolled in A536-04 (A536-06/MK-6143-004)
Official title: An Open-Label Extension Study To Evaluate The Long-Term Effects Of ACE-536 In Patients With β-Thalassemia Previously Enrolled In Study A536-04
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: β-Thalassemia
Lead sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Sponsor class: INDUSTRY
First posted: 2014-10-20
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Study A536-06 (MK-6143-004) is an open-label extension study for participants previously enrolled in study A536-04 (NCT01749540), to evaluate the long-term safety and tolerability of luspatercept in adult participants with beta-thalassemia.


Eligibility criteria: The main inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria:

* Completion of the treatment period in the base study A536-04.
* Females of child- bearing potential (defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal ≥24 consecutive months) must have negative urine or blood pregnancy test prior to enrollment and use adequate birth control methods (abstinence, oral contraceptives, barrier method with spermicide, or surgical sterilization) during study participation and for 12 weeks following the last dose of study drug
* Males must agree to use a latex condom during any sexual contact with females of child-bearing potential during study participation and for 12 weeks following the last dose of study drug, even if he has undergone a successful vasectomy
* Participants must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of study drug
* Participants with treatment interruption (defined as participants who complete the end of study visit for study A536-04 and are ≥28 days post end of study visit) must also meet the following criteria:
* Mean hemoglobin concentration \<10.0 g/dL of 2 measurements (not influenced by red blood cell \[RBC\] transfusion) (one performed within one day prior to first dose of study treatment and the other performed during the screening period \[Day -28 to Day -1\]) in non-transfusion dependent (NTD) participants
* Adequate folate levels or on folate therapy
* Platelet count ≥100 x 10\^9/L and ≤1,000 x 10\^9/L
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \<3 x upper limit of normal (ULN)
* Serum creatinine ≤ 1.5 x ULN
* Ejection fraction ≥50% by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA)

Exclusion Criteria:

* Discontinuation/withdrawal from study A536-04 due to participant request, participant unwillingness or inability to comply with the protocol, pregnancy, use of prohibited medication (e.g., hydroxyurea), medical reason or adverse event, hypersensitivity reaction to the study drug, at the discretion of the sponsor, or loss to follow-up prior to completion of the treatment period
* Any clinically significant pulmonary (including pulmonary hypertension), cardiovascular, endocrine, neurologic, hepatic, gastrointestinal, infectious, immunological (including clinically significant allo- or auto-immunization) or genitourinary disease considered by the investigator as not adequately controlled prior to the first dose of study trearment
* Symptomatic splenomegaly
* Splenectomy within 56 days prior to the first dose of study treatment
* Major surgery (except splenectomy) within 28 days prior to the first dose of study treatment. Participants must have completely recovered from any previous surgery prior to the first dose of study treatment
* Participants receiving or planning to receive hydroxyurea treatment. Participants must not have had hydroxyurea within 90 days of the first dose of study treatment
* For participants with treatment interruption: Iron chelation therapy if initiated within 56 days prior to the first dose of study treatment
* Cytotoxic agents, systemic corticosteroids, immunosuppressants, or anticoagulant therapy such as warfarin or heparin within 28 days prior to the first dose of study treatment (prophylactic aspirin up to 100 mg/day and low molecular weight (LMW) heparin for superficial vein thrombosis (SVT) is permitted)
* Treatment with another investigational drug (including sotatercept \[ACE-011\]) or device, or approved therapy for investigational use ≤28 days prior to the first dose of study treatment, or if the half-life of the previous investigational product is known, within 5 times the half-life prior to the first dose of study treatment, whichever is longer at any time between the end of treatment of the base study A536-04 and the first dose of study treatment
* Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B virus (HBV) or active infectious hepatitis C virus (HCV)
* Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥150 mm mercury (Hg) or diastolic blood pressure (DBP) ≥100 mm Hg
* Known history of thromboembolic events ≥Grade 3 according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0
* Pregnant or lactating females
* History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug

Primary outcomes:
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 68 months
measure: Number of Participants Who Discontinued Study Treatment Due To an AE
timeFrame: Up to approximately 60 months
Secondary outcomes:
measure: Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline Over a Rolling 8-week Interval
timeFrame: Any 8-week interval during the study (up to approximately 68 months)
measure: Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline Over a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 68 months)
measure: Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline During Weeks 13 to 24
timeFrame: Weeks 13 to 24
measure: Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline During Weeks 37 to 48
timeFrame: Weeks 37 to 48
measure: Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline Over a Rolling 8-week Interval
timeFrame: Any 8-week interval during the study (up to approximately 68 months)
measure: Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline Over a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 68 months)
measure: Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline During Weeks 13 to 24
timeFrame: Weeks 13 to 24
measure: Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline During Weeks 37 to 48
timeFrame: Weeks 37 to 48
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥20% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 8-week Interval
timeFrame: Any 8-week interval during the study (up to approximately 68 months)
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥33% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 8-Week Interval
timeFrame: Any 8-week interval during the study (up to approximately 68 months)
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥50% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 8-week Interval
timeFrame: Any 8-week interval during the study (up to approximately 68 months)
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥20% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 68 months)
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥33% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 12-Week Interval
timeFrame: Any 12-week interval during the study (up to approximately 68 months)
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥50% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 68 months)
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥20% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During Weeks 13 to 24
timeFrame: Weeks 13 to 24
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥33% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During Weeks 13 to 24
timeFrame: Weeks 13 to 24
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥50% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During Weeks 13 to 24
timeFrame: Weeks 13 to 24
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥20% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During Weeks 37 to 48
timeFrame: Weeks 37 to 48
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥33% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During Weeks 37 to 48
timeFrame: Weeks 37 to 48
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥50% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During Weeks 37 to 48
timeFrame: Weeks 37 to 48
measure: Percentage of Transfusion Dependent (TD) Participants Who Maintained Red Blood Cell (RBC) Transfusion Independence For ≥8 Weeks
timeFrame: Any 8-week interval during the study (up to approximately 68 months)
measure: Maximum Percent Change From Baseline in Red Blood Cell (RBC) Transfusions in Transfusion Dependent (TD) Participants Over 8 Weeks
timeFrame: Any 8-week interval during the study (up to approximately 68 months)
measure: Maximum Percent Change From Baseline in Red Blood Cell (RBC) Transfusions in Transfusion Dependent (TD) Participants Over 12 Weeks
timeFrame: Any 12-week interval during the study (up to approximately 68 months)
measure: Time To Erythroid Response for Non-transfusion Dependent (NTD) Participants Who Achieved a Hemoglobin Increase ≥1.0 g/dL Over a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 68 months)
measure: Time To Erythroid Response for Non-transfusion Dependent (NTD) Participants Who Achieved a Hemoglobin Increase ≥1.5 g/dL Over a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 68 months)
measure: Time To Erythroid Response for Transfusion Dependent (TD) Participants Who Achieved a Transfusion Burden Reduction of ≥33% Over a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 68 months)
measure: Time To Erythroid Response for Transfusion Dependent (TD) Participants Who Achieved a Transfusion Burden Reduction of ≥50% Over a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 68 months)
measure: Duration of Erythroid Response for Non-transfusion Dependent (NTD) Participants Who Achieved a Hemoglobin Increase ≥1.0 g/dL Over a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 68 months)
measure: Duration of Erythroid Response for Non-transfusion Dependent (NTD) Participants Who Achieved a Hemoglobin Increase ≥1.5 g/dL Over a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 68 months)
measure: Duration of Erythroid Response for Transfusion Dependent (TD) Participants Who Achieved a Transfusion Burden Reduction of ≥33% Over a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 68 months)
measure: Duration of Erythroid Response for Transfusion Dependent (TD) Participants Who Achieved a Transfusion Burden Reduction of ≥50% Over a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 68 months)
measure: Mean Change From Baseline in Pre-transfusion Hemoglobin Levels in Transfusion Dependent (TD) Participants
timeFrame: Any 8 or 12-week interval during the study (up to approximately 68 months)
measure: Mean Change From Baseline in Hemoglobin Level Over Multiple Rolling 8-Week Intervals in Non-transfusion Dependent (NTD) Participants
timeFrame: Baseline (prior to first dose of study drug) and multiple 8-week intervals during the study (up to approximately 68 months)
measure: Mean Change From Baseline in Hemoglobin Level Over Multiple Rolling 12-Week Intervals in Non-transfusion Dependent (NTD) Participants
timeFrame: Baseline (prior to first dose of study drug) and multiple 12-week intervals during the study (up to approximately 68 months)
measure: Percent Change From Baseline in Transfusion Burden Over Multiple Rolling 8-Week Intervals in Transfusion Dependent (TD) Participants
timeFrame: Baseline (prior to first dose of study drug) and multiple 8-week intervals during the study (up to approximately 68 months)
measure: Percent Change From Baseline in Transfusion Burden Over Multiple Rolling 12-Week Intervals in Transfusion Dependent (TD) Participants
timeFrame: Baseline (prior to first dose of study drug) and multiple 12-week intervals during the study (up to approximately 68 months)
measure: Percent Change From Baseline to End of Treatment in Erythropoietin
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
measure: Percent Change From Baseline to End of Treatment in Reticulocyte Count
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
measure: Percent Change From Baseline to End of Treatment in Nucleated Red Blood Cell (nRBC) Count
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
measure: Percent Change From Baseline to End of Treatment in Soluble Transferrin Receptor
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
measure: Percent Change From Baseline to End of Treatment in Serum Ferritin
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
measure: Percent Change From Baseline to End of Treatment in Percent Transferrin (Iron) Saturation
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
measure: Percent Change From Baseline to End of Treatment in Serum Transferrin
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
measure: Percent Change From Baseline to End of Treatment in Serum Iron
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
measure: Percent Change From Baseline to End of Treatment in Serum Hepcidin
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
measure: Percent Change From Baseline to End of Treatment in Serum Total Iron Binding Capacity (TIBC)
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
measure: Percent Change From Baseline to End of Treatment in Non-transferrin Bound Iron (NTBI)
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
measure: Percent Change From Baseline to End of Treatment in Total Bilirubin
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
measure: Percent Change From Baseline to End of Treatment in Indirect Bilirubin
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
measure: Percent Change From Baseline to End of Treatment in Lactate Dehydrogenase (LDH)
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
measure: Change From Baseline in Liver Iron Concentration (LIC) For Participants With Baseline LIC <3 mg/g Dry Weight Measured After 18 Months and Up to 60 Months of Treatment
timeFrame: Baseline (prior to first dose of study drug) and up to approximately 60 Months
measure: Change From Baseline in Liver Iron Concentration (LIC) For Participants With Baseline LIC ≥3 mg/g Dry Weight Measured After 18 Months and Up to 60 Months of Treatment
timeFrame: Baseline (prior to first dose of study drug) and up to approximately 60 Months
measure: Change From Baseline in Liver Iron Concentration (LIC) For Participants With Baseline LIC <3 mg/g Dry Weight, Who Have Used Iron Chelation Therapy (ICT), Measured After 18 Months and Up to 60 Months of Treatment
timeFrame: Baseline (prior to first dose of study drug) and up to approximately 60 Months
measure: Change From Baseline in Liver Iron Concentration (LIC) For Participants With Baseline LIC ≥3 mg/g Dry Weight, Who Have Used Iron Chelation Therapy (ICT), Measured After 18 Months and Up to 60 Months of Treatment
timeFrame: Baseline (prior to first dose of study drug) and up to approximately 60 Months
measure: Change From Baseline in Liver Iron Concentration (LIC) For Participants With Baseline LIC <3 mg/g Dry Weight, Who Have Not Used Iron Chelation Therapy (ICT), Measured After 18 Months and Up to 60 Months of Treatment
timeFrame: Baseline (prior to first dose of study drug) and up to approximately 60 Months
measure: Change From Baseline in Liver Iron Concentration (LIC) For Participants With Baseline LIC ≥3 mg/g Dry Weight, Who Have Not Used Iron Chelation Therapy (ICT), Measured After 18 Months and Up to 60 Months of Treatment
timeFrame: Baseline (prior to first dose of study drug) and up to approximately 60 Months
measure: Serum Concentration of Luspatercept
timeFrame: Predose and Postdose Days 1, 8, 22, 169, 176, 190, 337, and 344
Other outcomes:
Locations:
city: Athens
country: Greece
facility: Acceleron Investigative Site
city: Brindisi
country: Italy
facility: Acceleron Investigative Site
city: Catania
country: Italy
facility: Acceleron Investigative Site
city: Ferrara
country: Italy
facility: Acceleron Investigative Site
city: Modena
country: Italy
facility: Acceleron Investigative Site
city: Naples
country: Italy
facility: Acceleron Investigative Site
city: Turin
country: Italy
facility: Acceleron Investigative Site
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Piga A, Perrotta S, Gamberini MR, Voskaridou E, Melpignano A, Filosa A, Caruso V, Pietrangelo A, Longo F, Tartaglione I, Borgna-Pignatti C, Zhang X, Laadem A, Sherman ML, Attie KM. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with beta-thalassemia. Blood. 2019 Mar 21;133(12):1279-1289. doi: 10.1182/blood-2018-10-879247. Epub 2019 Jan 7.