A Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants With Non-transfusion-dependent Thalassemia

Sponsor
Agios Pharmaceuticals, Inc. (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT03692052
Collaborator
(none)
20
4
1
141.1
5
0

Study Details

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
20 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Dec 28, 2018
Actual Primary Completion Date :
Aug 20, 2020
Anticipated Study Completion Date :
Sep 30, 2030

Arms and Interventions

Arm Intervention/Treatment
Experimental: AG-348

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.

Drug: AG-348
AG-348 tablet orally BID
Other Names:
  • Mitapivat
  • Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants Achieving a Hemoglobin Response (HR) [Up to 12 weeks]

      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

    1. Average Change From Baseline in Hb Concentrations From Week 12 to Week 24 [Baseline, 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.

    2. Percentage of Participants Achieving a Sustained Hb Response (sHR) [Week 12 to Week 24]

      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.

    3. Percentage of Participants Achieving a Delayed Hb Response [Week 12 to Week 24]

      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.

    4. Change From Baseline in Hb Concentration Over the Duration of the Extension Period [Baseline up to approximately 10.5 years]

    5. Time to First ≥1.0 g/dL Increase in Hb Concentration [Up to Week 24]

    6. Change From Baseline in Reticulocyte Count [Up to approximately 10.5 years]

    7. Change From Baseline in Bilirubin [Up to approximately 10.5 years]

    8. Change From Baseline in Lactate Dehydrogenase (LDH) [Up to approximately 10.5 years]

    9. Change From Baseline in Haptoglobin [Up to approximately 10.5 years]

    10. Change From Baseline in Nucleated Red Blood Cells (NRBCs) [Up to approximately 10.5 years]

    11. Change From Baseline in Erythropoietin (EPO) [Up to approximately 10.5 years]

    12. Change From Baseline in Soluble Transferrin Receptor [Up to approximately 10.5 years]

    13. Drug Concentrations Over Time for AG-348 [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]

    14. AUC0-8h: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours of AG-348 [Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12]

    15. AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration of AG-348 [Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12]

    16. Cmax: Maximum Observed Plasma Concentration of AG-348 [Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12]

    17. Tmax: Time to Reach the Maximum Plasma Radioactivity Concentration (Cmax) [Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12]

    18. Tlast: Time of the Last Quantifiable Concentration of AG-348 [Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12]

    19. Ctrough: Observed Plasma Concentration at the End of a Dosing Interval of AG-348 [Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12]

    20. 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 [From signing the inform consent form up to data cut-off date: 20 August 2020 (Up to approximately 19 months)]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 UCSF Benioff Children's Hospital Oakland Oakland California United States 94609
    2 Massachusetts General Hospital Boston Massachusetts United States 02114
    3 University Health Network (Toronto General Hospital) Toronto Ontario Canada M5G 2C4
    4 Imperial College Healthcare NHS Trust (Hammersmith Hospital) London United Kingdom W12 0HS

    Sponsors and Collaborators

    • Agios Pharmaceuticals, Inc.

    Investigators

    • Study Chair: Medical Affairs, Agios Pharmaceuticals, Inc.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Agios Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT03692052
    Other Study ID Numbers:
    • AG348-C-010
    • 2018-002217-35
    First Posted:
    Oct 2, 2018
    Last Update Posted:
    Jul 25, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details Participants took part in the study at 4 investigative sites in the United States, Canada, and United Kingdom from 28 December 2018 to 30 September 2030. Results are reported for the primary and secondary outcome measures for the 24-week Core Period (data cut-off date: 20 August 2020). The Extension Period of this study is ongoing.
    Pre-assignment Detail A total of 20 participants were enrolled in the Core Period of this study. The participants who completed the 24-week Core Period and achieved a hemoglobin (Hb) response or a delayed Hb response and had an acceptable safety profile were eligible to continue in the Extension Period.
    Arm/Group Title AG-348
    Arm/Group 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.
    Period Title: Core Period (Day 1 to Week 24)
    STARTED 20
    COMPLETED 19
    NOT COMPLETED 1
    Period Title: Core Period (Day 1 to Week 24)
    STARTED 19
    COMPLETED 0
    NOT COMPLETED 19

    Baseline Characteristics

    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    Overall Participants 20
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    45.3
    (11.81)
    Sex: Female, Male (Count of Participants)
    Female
    15
    75%
    Male
    5
    25%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    Not Hispanic or Latino
    19
    95%
    Unknown or Not Reported
    1
    5%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    10
    50%
    Native Hawaiian or Other Pacific Islander
    1
    5%
    Black or African American
    1
    5%
    White
    4
    20%
    More than one race
    0
    0%
    Unknown or Not Reported
    4
    20%

    Outcome Measures

    1. Primary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    FAS included all participants who received at least 1 dose of study treatment.
    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    Measure Participants 20
    Number (90% Confidence Interval) [percentage of participants]
    80.0
    400%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection AG-348
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <.0001
    Comments
    Method Clopper-Pearson Method
    Comments Significance of p-value associated with the test of H0:Hb response rate =0.3 vs H1:Hb response rate > 0.3.
    2. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    FAS included all participants who received at least 1 dose of study treatment. Number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    Measure Participants 20
    Baseline
    79.44
    (13.690)
    Average Change from Baseline: Week 12 to 24
    13.01
    (6.283)
    3. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    FAS included all participants who received at least 1 dose of study treatment.
    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    Measure Participants 20
    Number (90% Confidence Interval) [percentage of participants]
    65.0
    325%
    4. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    FAS included all participants who received at least 1 dose of study treatment.
    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    Measure Participants 20
    Number (90% Confidence Interval) [percentage of participants]
    10.0
    50%
    5. Secondary Outcome
    Title Change From Baseline in Hb Concentration Over the Duration of the Extension Period
    Description
    Time Frame Baseline up to approximately 10.5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    6. Secondary Outcome
    Title Time to First ≥1.0 g/dL Increase in Hb Concentration
    Description
    Time Frame Up to Week 24

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS) included all participants who received at least 1 dose of study treatment. Data is reported for the responders.
    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    Measure Participants 16
    Mean (Standard Deviation) [weeks]
    4.54
    (3.204)
    7. Secondary Outcome
    Title Change From Baseline in Reticulocyte Count
    Description
    Time Frame Up to approximately 10.5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    8. Secondary Outcome
    Title Change From Baseline in Bilirubin
    Description
    Time Frame Up to approximately 10.5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    9. Secondary Outcome
    Title Change From Baseline in Lactate Dehydrogenase (LDH)
    Description
    Time Frame Up to approximately 10.5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    10. Secondary Outcome
    Title Change From Baseline in Haptoglobin
    Description
    Time Frame Up to approximately 10.5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    11. Secondary Outcome
    Title Change From Baseline in Nucleated Red Blood Cells (NRBCs)
    Description
    Time Frame Up to approximately 10.5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    12. Secondary Outcome
    Title Change From Baseline in Erythropoietin (EPO)
    Description
    Time Frame Up to approximately 10.5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    13. Secondary Outcome
    Title Change From Baseline in Soluble Transferrin Receptor
    Description
    Time Frame Up to approximately 10.5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    14. Secondary Outcome
    Title Drug Concentrations Over Time for AG-348
    Description
    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

    Outcome Measure Data

    Analysis Population Description
    The Pharmacokinetic (PK) Analysis Set included all participants who were enrolled and received a dose of study medication (AG-348), with at least one non-zero plasma concentration of AG-348 at Day 1 or Week 12 (or the Unscheduled Visit where intensive PK samples were assessed). Number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    Measure Participants 20
    AG-348 50 mg: 0.00 Hour, Day 1
    NA
    (NA)
    AG-348 50 mg: 0.50 Hour, Day 1
    NA
    (NA)
    AG-348 50 mg: 1 Hour, Day 1
    785.2
    (64.6)
    AG-348 50 mg: 2 Hour, Day 1
    694.5
    (26.6)
    AG-348 50 mg: 4 Hour, Day 1
    369.2
    (29.4)
    AG-348 50 mg: 8 Hour, Day 1
    128.9
    (55.1)
    AG-348 100 mg: 0.00 Hour, Week 12
    39.39
    (117.1)
    AG-348 100 mg: 0.50 Hour, Week 12
    1030
    (137.7)
    AG-348 100 mg: 1 Hour, Week 12
    1442
    (30.6)
    AG-348 100 mg: 2 Hour, Week 12
    740.1
    (76.3)
    AG-348 100 mg: 4 Hour, Week 12
    302.8
    (75.2)
    AG-348 100 mg: 8 Hour, Week 12
    77.35
    (48.2)
    15. Secondary Outcome
    Title AUC0-8h: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours of AG-348
    Description
    Time Frame Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12

    Outcome Measure Data

    Analysis Population Description
    The PK Analysis Set included all participants who were enrolled and received a dose of study medication (AG-348), with at least one non-zero plasma concentration of AG-348 at Day 1 or Week 12 (or the Unscheduled Visit where intensive PK samples were assessed). Number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    Measure Participants 20
    AG-348 50 mg: Day 1
    3083.3
    (25.6)
    AG-348 100 mg: Week 12
    3384.4
    (65.7)
    16. Secondary Outcome
    Title AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration of AG-348
    Description
    Time Frame Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12

    Outcome Measure Data

    Analysis Population Description
    The PK Analysis Set included all participants who were enrolled and received a dose of study medication (AG-348), with at least one non-zero plasma concentration of AG-348 at Day 1 or Week 12 (or the Unscheduled Visit where intensive PK samples were assessed). Number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    Measure Participants 20
    AG-348 50 mg: Day 1
    3083.5
    (25.6)
    AG-348 100 mg: Week 12
    3384.4
    (65.7)
    17. Secondary Outcome
    Title Cmax: Maximum Observed Plasma Concentration of AG-348
    Description
    Time Frame Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12

    Outcome Measure Data

    Analysis Population Description
    The PK Analysis Set included all participants who were enrolled and received a dose of study medication (AG-348), with at least one non-zero plasma concentration of AG-348 at Day 1 or Week 12 (or the Unscheduled Visit where intensive PK samples were assessed). Number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    Measure Participants 20
    AG-348 50 mg: Day 1
    968.9
    (38.1)
    AG-348 100 mg: Week 12
    1476
    (93.5)
    18. Secondary Outcome
    Title Tmax: Time to Reach the Maximum Plasma Radioactivity Concentration (Cmax)
    Description
    Time Frame Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12

    Outcome Measure Data

    Analysis Population Description
    The PK Analysis Set included all participants who were enrolled and received a dose of study medication (AG-348), with at least one non-zero plasma concentration of AG-348 at Day 1 or Week 12 (or the Unscheduled Visit where intensive PK samples were assessed). Number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    Measure Participants 20
    AG-348 50 mg: Day 1
    1.07
    AG-348 100 mg: Week 12
    0.53
    19. Secondary Outcome
    Title Tlast: Time of the Last Quantifiable Concentration of AG-348
    Description
    Time Frame Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12

    Outcome Measure Data

    Analysis Population Description
    The PK Analysis Set included all participants who were enrolled and received a dose of study medication (AG-348), with at least one non-zero plasma concentration of AG-348 at Day 1 or Week 12 (or the Unscheduled Visit where intensive PK samples were assessed). Number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    Measure Participants 20
    AG-348 50 mg: Day 1
    7.60
    AG-348 100 mg: Week 12
    7.55
    20. Secondary Outcome
    Title Ctrough: Observed Plasma Concentration at the End of a Dosing Interval of AG-348
    Description
    Time Frame Predose (60 minutes) and 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours postdose on Day 1 and Week 12

    Outcome Measure Data

    Analysis Population Description
    The PK Analysis Set included all participants who were enrolled and received a dose of study medication (AG-348), with at least one non-zero plasma concentration of AG-348 at Day 1 or Week 12 (or the Unscheduled Visit where intensive PK samples were assessed). Number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    Measure Participants 20
    AG-348 100 mg: Week 12
    37.34
    (117.7)
    21. Secondary Outcome
    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)

    Outcome Measure Data

    Analysis Population Description
    Safety Analysis Set included all participants who received at least 1 dose of study treatment.
    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    Measure Participants 20
    TEAEs
    85.0
    425%
    SAEs
    5.0
    25%
    AESIs
    5.0
    25%
    TEAEs Leading to Study Drug Dose Reduction
    15.0
    75%
    TEAEs Leading to Study Drug Interruption
    5.0
    25%
    TEAEs Leading to Study Drug Discontinuation
    5.0
    25%

    Adverse Events

    Time Frame Up to completion of the Core Period data cut-off date: 20 August 2020 (Up to approximately 19 months)
    Adverse Event Reporting Description Safety Analysis Set included all participants who received at least 1 dose of study treatment.
    Arm/Group Title AG-348
    Arm/Group Description Participants with alpha or beta thalassemia received AG-348 50 mg BID, orally up to Week 6. Following Week 6, depending on the participants' safety and 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.
    All Cause Mortality
    AG-348
    Affected / at Risk (%) # Events
    Total 0/20 (0%)
    Serious Adverse Events
    AG-348
    Affected / at Risk (%) # Events
    Total 1/20 (5%)
    Renal and urinary disorders
    Renal impairment 1/20 (5%)
    Other (Not Including Serious) Adverse Events
    AG-348
    Affected / at Risk (%) # Events
    Total 17/20 (85%)
    Blood and lymphatic system disorders
    Anaemia 1/20 (5%)
    Lymphadenopathy 1/20 (5%)
    Cardiac disorders
    Palpitations 1/20 (5%)
    Tachycardia 1/20 (5%)
    Ear and labyrinth disorders
    Vertigo positional 1/20 (5%)
    Ear pain 1/20 (5%)
    Gastrointestinal disorders
    Dyspepsia 4/20 (20%)
    Abdominal pain 3/20 (15%)
    Diarrhoea 3/20 (15%)
    Abdominal distension 3/20 (15%)
    Nausea 3/20 (15%)
    Abdominal pain upper 2/20 (10%)
    Vomiting 2/20 (10%)
    Constipation 1/20 (5%)
    Dry mouth 1/20 (5%)
    Gingival pain 1/20 (5%)
    Haemorrhoids 1/20 (5%)
    Oral pain 1/20 (5%)
    Flatulence 1/20 (5%)
    General disorders
    Fatigue 4/20 (20%)
    Pain 3/20 (15%)
    Chest discomfort 2/20 (10%)
    Pyrexia 2/20 (10%)
    Oedema peripheral 1/20 (5%)
    Non-cardiac chest pain 1/20 (5%)
    Hepatobiliary disorders
    Ocular icterus 3/20 (15%)
    Infections and infestations
    Upper respiratory tract infection 4/20 (20%)
    Body tinea 1/20 (5%)
    Conjunctivitis 1/20 (5%)
    Oral herpes 1/20 (5%)
    Sinusitis 1/20 (5%)
    Viral upper respiratory tract infection 1/20 (5%)
    Herpes simplex 1/20 (5%)
    Suspected COVID-19 1/20 (5%)
    Injury, poisoning and procedural complications
    Limb injury 1/20 (5%)
    Investigations
    Aspartate aminotransferase increased 1/20 (5%)
    Electrocardiogram QT prolonged 1/20 (5%)
    Fibrin D dimer increased 1/20 (5%)
    Metabolism and nutrition disorders
    Decreased appetite 1/20 (5%)
    Musculoskeletal and connective tissue disorders
    Pain in extremity 3/20 (15%)
    Back pain 2/20 (10%)
    Arthralgia 1/20 (5%)
    Joint range of motion decreased 1/20 (5%)
    Joint swelling 1/20 (5%)
    Muscle spasms 1/20 (5%)
    Muscular weakness 1/20 (5%)
    Sjogren's syndrome 1/20 (5%)
    Temporomandibular joint syndrome 1/20 (5%)
    Tendonitis 1/20 (5%)
    Nervous system disorders
    Dizziness 6/20 (30%)
    Headache 5/20 (25%)
    Carotid arteriosclerosis 1/20 (5%)
    Hypoaesthesia 1/20 (5%)
    Nystagmus 1/20 (5%)
    Presyncope 1/20 (5%)
    Syncope 1/20 (5%)
    Taste disorder 1/20 (5%)
    Psychiatric disorders
    Initial insomnia 10/20 (50%)
    Anxiety 1/20 (5%)
    Middle insomnia 1/20 (5%)
    Restlessness 1/20 (5%)
    Terminal insomnia 1/20 (5%)
    Renal and urinary disorders
    Dysuria 1/20 (5%)
    Polyuria 1/20 (5%)
    Renal artery stenosis 1/20 (5%)
    Reproductive system and breast disorders
    Vulvovaginal pruritus 1/15 (6.7%)
    Respiratory, thoracic and mediastinal disorders
    Cough 4/20 (20%)
    Nasal congestion 4/20 (20%)
    Oropharyngeal pain 3/20 (15%)
    Dyspnoea 1/20 (5%)
    Sneezing 1/20 (5%)
    Upper-airway cough syndrome 1/20 (5%)
    Skin and subcutaneous tissue disorders
    Rash erythematous 2/20 (10%)
    Rash 2/20 (10%)
    Dermatitis contact 1/20 (5%)
    Night sweats 1/20 (5%)
    Pruritus 1/20 (5%)
    Skin odour abnormal 1/20 (5%)
    Vascular disorders
    Hypotension 1/20 (5%)
    Hot flush 1/20 (5%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The information obtained from the clinical study will be used towards the development of AG-348 and may be disclosed to regulatory authority(ies), other Investigators, corporate partners, or consultants as required.

    Results Point of Contact

    Name/Title Medical Affairs
    Organization Agios Pharmaceuticals, Inc.
    Phone 833-228-8474
    Email medinfo@agios.com
    Responsible Party:
    Agios Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT03692052
    Other Study ID Numbers:
    • AG348-C-010
    • 2018-002217-35
    First Posted:
    Oct 2, 2018
    Last Update Posted:
    Jul 25, 2022
    Last Verified:
    Jul 1, 2022