Back to resultsA Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants With Non-transfusion-dependent Thalassemia
Primary Purpose
Thalassemia
Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
AG-348
Sponsored by
About this trial
This is an interventional treatment trial for Thalassemia
Eligibility Criteria
Inclusion Criteria:
- Informed consent;
- Known medical history of thalassemia, including β-thalassemia intermedia, Hb E β-thalassemia, α-thalassemia (Hb H disease), or β-thalassemia with mutations of 1 or more α genes;
- Documented clinical laboratory confirmation of thalassemia by Hb electrophoresis/high-performance liquid chromatography (HPLC) or deoxyribonucleic acid (DNA) analysis, either from medical records or during the screening period;
- Hb concentration ≤10.0 grams per deciliter (g/dL), regardless of sex, based on an average of at least 2 Hb measurements (separated by a minimum of 7 days) during the screening period;
- Considered non-transfusion-dependent, defined as having no more than 5 units of red blood cells (RBCs) transfused during the 24-week period up to the first day of study drug and no RBC transfusions in the 8 weeks prior to the first day of study drug;
- Adequate organ function;
- For women of reproductive potential: negative serum pregnancy test during the screening period and a negative serum or urine pregnancy test on Day 1;
- For women of reproductive potential as well as men with partners who are women of reproductive potential: be abstinent as part of their usual lifestyle, or agreement to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of giving informed consent, during the study, and for 28 days following the last dose of study drug for women and 90 days following the last dose of study drug for men;
- Willingness to comply with all study procedures for the duration of the study;
Exclusion Criteria:
- Known history of diagnosis of Hb S or Hb C forms of thalassemia;
- Significant medical condition that confers an unacceptable risk to participating in the study, and/or could confound the interpretation of the study data;
- Splenectomy scheduled during the study treatment period or having undergone splenectomy within 12 months prior to signing informed consent;
- Currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo;
- Exposure to any investigational drug, device, or procedure within 3 months prior to the first day of study drug;
- Prior exposure to sotatercept (ACE-011), luspatercept (ACE-536), ruxolitinib, or gene therapy;
- Prior bone marrow or stem cell transplant;
- Currently pregnant or breastfeeding;
- History of major surgery within 6 months of signing informed consent;
- Currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to the first day of study drug;
- Currently receiving chronic anticoagulant therapy, unless started and on a stable dose for at least 28 days prior to first day of study drug;
- Currently receiving anabolic steroids, including testosterone preparations, if initiated ≤28 days prior to the first day of study drug;
- Currently receiving hematopoietic stimulating agents (e.g., erythropoietins, granulocyte colony stimulating factors, thrombopoietins), if initiated ≤8 weeks prior to the first day of study drug;
- History of allergy to sulfonamides if characterized by acute hemolytic anemia, drug-induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis, or other serious clinical manifestations;
- History of allergy to AG-348 or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol).
Sites / Locations
- UCSF Benioff Children's Hospital Oakland
- Massachusetts General Hospital
- University Health Network (Toronto General Hospital)
- Imperial College Healthcare NHS Trust (Hammersmith Hospital)
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
AG-348
Arm Description
Participants with alpha or beta thalassemia received AG-348 50 mg twice daily (BID), orally up to Week 6. Following Week 6, depending on the participants' safety and hemoglobin (Hb) concentrations, they could undergo one potential dose-level increase from 50 to 100 mg BID. After completion of the Core Period of 24 weeks, participants were eligible to continue to receive AG-348 in the Extension Period which is up to 10 years.
Outcomes
Primary Outcome Measures
Percentage of Participants Achieving a Hemoglobin Response (HR)
HR was defined as a ≥1.0 gram per deciliter (g/dL) increase in Hb concentration from Baseline at 1 or more assessments between Week 4 and Week 12 (inclusive). A participant's Baseline Hb concentration was defined as the average of all the participant's available Hb concentrations during the screening period up to the first dose of study drug.
Secondary Outcome Measures
Average Change From Baseline in Hb Concentrations From Week 12 to Week 24
A participant's Baseline Hb concentration was defined as the average of all the participant's available Hb concentrations during the screening period up to the first dose of study drug.
Percentage of Participants Achieving a Sustained Hb Response (sHR)
sHR was defined as achieving HR and achieving a ≥1.0 g/deciliter (dL) increase in Hb concentration at 2 or more evaluable Hb assessments out of the 4 scheduled assessments between the Week 12 visit and Week 24 visit.
Percentage of Participants Achieving a Delayed Hb Response
Delayed Hb response was defined as not achieving HR and achieving a ≥1.0 g/dL increase in Hb concentration at 1 or more Hb assessments after Week 12.
Change From Baseline in Hb Concentration Over the Duration of the Extension Period
Time to First ≥1.0 g/dL Increase in Hb Concentration
Change From Baseline in Reticulocyte Count
Change From Baseline in Bilirubin
Change From Baseline in Lactate Dehydrogenase (LDH)
Change From Baseline in Haptoglobin
Change From Baseline in Nucleated Red Blood Cells (NRBCs)
Change From Baseline in Erythropoietin (EPO)
Change From Baseline in Soluble Transferrin Receptor
Drug Concentrations Over Time for AG-348
AUC0-8h: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours of AG-348
AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration of AG-348
Cmax: Maximum Observed Plasma Concentration of AG-348
Tmax: Time to Reach the Maximum Plasma Radioactivity Concentration (Cmax)
Tlast: Time of the Last Quantifiable Concentration of AG-348
Ctrough: Observed Plasma Concentration at the End of a Dosing Interval of AG-348
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), and TEAEs Leading to Study Drug Dose Reduction, Study Drug Interruption, and Study Drug Discontinuation
An AE is any unfavorable and unintended sign, symptom, or disease, whether or not related to the investigational product. A TEAE was defined as any AE with onset post study drug treatment. An SAE was defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically important. AESIs are predefined AEs that required close monitoring and prompt reporting to the sponsor. AESIs included protocol-specified transaminase increase.
Full Information
NCT ID
NCT03692052
First Posted
September 10, 2018
Last Updated
October 10, 2023
Sponsor
Agios Pharmaceuticals, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT03692052
Brief Title
A Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants With Non-transfusion-dependent Thalassemia
Official Title
A Phase 2, Open-label, Multicenter Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Subjects With Non-transfusion-dependent Thalassemia
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 20, 2019 (Actual)
Primary Completion Date
August 20, 2020 (Actual)
Study Completion Date
September 30, 2030 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Agios Pharmaceuticals, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
Study AG348-C-010 is a multicenter study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of treatment with AG-348 in adult participants with non-transfusion-dependent thalassemia (NTDT). This study includes a core period (up to 24 weeks) followed by an extension period (up to 10 years) for eligible participants. 20 participants with NTDT were enrolled. The initial dose of AG-348 was 50 milligrams (mg) twice daily (BID) with one potential dose-level increase to 100 mg BID at the Week 6 visit based on the participant's safety and hemoglobin (Hb) concentrations.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Thalassemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)
8. Arms, Groups, and Interventions
Arm Title
AG-348
Arm Type
Experimental
Arm Description
Participants with alpha or beta thalassemia received AG-348 50 mg twice daily (BID), orally up to Week 6. Following Week 6, depending on the participants' safety and hemoglobin (Hb) concentrations, they could undergo one potential dose-level increase from 50 to 100 mg BID. After completion of the Core Period of 24 weeks, participants were eligible to continue to receive AG-348 in the Extension Period which is up to 10 years.
Intervention Type
Drug
Intervention Name(s)
AG-348
Other Intervention Name(s)
Mitapivat
Intervention Description
AG-348 tablet orally BID
Primary Outcome Measure Information:
Title
Percentage of Participants Achieving a Hemoglobin Response (HR)
Description
HR was defined as a ≥1.0 gram per deciliter (g/dL) increase in Hb concentration from Baseline at 1 or more assessments between Week 4 and Week 12 (inclusive). A participant's Baseline Hb concentration was defined as the average of all the participant's available Hb concentrations during the screening period up to the first dose of study drug.
Time Frame
Up to 12 weeks
Secondary Outcome Measure Information:
Title
Average Change From Baseline in Hb Concentrations From Week 12 to Week 24
Description
A participant's Baseline Hb concentration was defined as the average of all the participant's available Hb concentrations during the screening period up to the first dose of study drug.
Time Frame
Baseline, Week 12 to Week 24
Title
Percentage of Participants Achieving a Sustained Hb Response (sHR)
Description
sHR was defined as achieving HR and achieving a ≥1.0 g/deciliter (dL) increase in Hb concentration at 2 or more evaluable Hb assessments out of the 4 scheduled assessments between the Week 12 visit and Week 24 visit.
Time Frame
Week 12 to Week 24
Title
Percentage of Participants Achieving a Delayed Hb Response
Description
Delayed Hb response was defined as not achieving HR and achieving a ≥1.0 g/dL increase in Hb concentration at 1 or more Hb assessments after Week 12.
Time Frame
Week 12 to Week 24
Title
Change From Baseline in Hb Concentration Over the Duration of the Extension Period
Time Frame
Baseline up to approximately 10.5 years
Title
Time to First ≥1.0 g/dL Increase in Hb Concentration
Time Frame
Up to Week 24
Title
Change From Baseline in Reticulocyte Count
Time Frame
Up to approximately 10.5 years
Title
Change From Baseline in Bilirubin
Time Frame
Up to approximately 10.5 years
Title
Change From Baseline in Lactate Dehydrogenase (LDH)
Time Frame
Up to approximately 10.5 years
Title
Change From Baseline in Haptoglobin
Time Frame
Up to approximately 10.5 years
Title
Change From Baseline in Nucleated Red Blood Cells (NRBCs)
Time Frame
Up to approximately 10.5 years
Title
Change From Baseline in Erythropoietin (EPO)
Time Frame
Up to approximately 10.5 years
Title
Change From Baseline in Soluble Transferrin Receptor
Time Frame
Up to approximately 10.5 years
Title
Drug Concentrations Over Time for AG-348
Time Frame
Predose (60 minutes) and 0.00 hour, 0.50 hour, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12
Title
AUC0-8h: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours of AG-348
Time Frame
Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12
Title
AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration of AG-348
Time Frame
Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12
Title
Cmax: Maximum Observed Plasma Concentration of AG-348
Time Frame
Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12
Title
Tmax: Time to Reach the Maximum Plasma Radioactivity Concentration (Cmax)
Time Frame
Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12
Title
Tlast: Time of the Last Quantifiable Concentration of AG-348
Time Frame
Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12
Title
Ctrough: Observed Plasma Concentration at the End of a Dosing Interval of AG-348
Time Frame
Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12
Title
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), and TEAEs Leading to Study Drug Dose Reduction, Study Drug Interruption, and Study Drug Discontinuation
Description
An AE is any unfavorable and unintended sign, symptom, or disease, whether or not related to the investigational product. A TEAE was defined as any AE with onset post study drug treatment. An SAE was defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically important. AESIs are predefined AEs that required close monitoring and prompt reporting to the sponsor. AESIs included protocol-specified transaminase increase.
Time Frame
From signing the inform consent form up to data cut-off date: 20 August 2020 (Up to approximately 19 months)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Informed consent;
Known medical history of thalassemia, including β-thalassemia intermedia, Hb E β-thalassemia, α-thalassemia (Hb H disease), or β-thalassemia with mutations of 1 or more α genes;
Documented clinical laboratory confirmation of thalassemia by Hb electrophoresis/high-performance liquid chromatography (HPLC) or deoxyribonucleic acid (DNA) analysis, either from medical records or during the screening period;
Hb concentration ≤10.0 grams per deciliter (g/dL), regardless of sex, based on an average of at least 2 Hb measurements (separated by a minimum of 7 days) during the screening period;
Considered non-transfusion-dependent, defined as having no more than 5 units of red blood cells (RBCs) transfused during the 24-week period up to the first day of study drug and no RBC transfusions in the 8 weeks prior to the first day of study drug;
Adequate organ function;
For women of reproductive potential: negative serum pregnancy test during the screening period and a negative serum or urine pregnancy test on Day 1;
For women of reproductive potential as well as men with partners who are women of reproductive potential: be abstinent as part of their usual lifestyle, or agreement to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of giving informed consent, during the study, and for 28 days following the last dose of study drug for women and 90 days following the last dose of study drug for men;
Willingness to comply with all study procedures for the duration of the study;
Exclusion Criteria:
Known history of diagnosis of Hb S or Hb C forms of thalassemia;
Significant medical condition that confers an unacceptable risk to participating in the study, and/or could confound the interpretation of the study data;
Splenectomy scheduled during the study treatment period or having undergone splenectomy within 12 months prior to signing informed consent;
Currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo;
Exposure to any investigational drug, device, or procedure within 3 months prior to the first day of study drug;
Prior exposure to sotatercept (ACE-011), luspatercept (ACE-536), ruxolitinib, or gene therapy;
Prior bone marrow or stem cell transplant;
Currently pregnant or breastfeeding;
History of major surgery within 6 months of signing informed consent;
Currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to the first day of study drug;
Currently receiving chronic anticoagulant therapy, unless started and on a stable dose for at least 28 days prior to first day of study drug;
Currently receiving anabolic steroids, including testosterone preparations, if initiated ≤28 days prior to the first day of study drug;
Currently receiving hematopoietic stimulating agents (e.g., erythropoietins, granulocyte colony stimulating factors, thrombopoietins), if initiated ≤8 weeks prior to the first day of study drug;
History of allergy to sulfonamides if characterized by acute hemolytic anemia, drug-induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis, or other serious clinical manifestations;
History of allergy to AG-348 or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Affairs
Organizational Affiliation
Agios Pharmaceuticals, Inc.
Official's Role
Study Chair
Facility Information:
Facility Name
UCSF Benioff Children's Hospital Oakland
City
Oakland
State/Province
California
ZIP/Postal Code
94609
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
University Health Network (Toronto General Hospital)
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2C4
Country
Canada
Facility Name
Imperial College Healthcare NHS Trust (Hammersmith Hospital)
City
London
ZIP/Postal Code
W12 0HS
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
35964609
Citation
Kuo KHM, Layton DM, Lal A, Al-Samkari H, Bhatia J, Kosinski PA, Tong B, Lynch M, Uhlig K, Vichinsky EP. Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion dependent alpha-thalassaemia or beta-thalassaemia: an open-label, multicentre, phase 2 study. Lancet. 2022 Aug 13;400(10351):493-501. doi: 10.1016/S0140-6736(22)01337-X.
Results Reference
derived
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A Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants With Non-transfusion-dependent Thalassemia
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