A Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants With Non-transfusion-dependent Thalassemia
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
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:
|
Outcome Measures
Primary Outcome Measures
- 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
- 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.
- 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.
- 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.
- Change From Baseline in Hb Concentration Over the Duration of the Extension Period [Baseline up to approximately 10.5 years]
- Time to First ≥1.0 g/dL Increase in Hb Concentration [Up to Week 24]
- Change From Baseline in Reticulocyte Count [Up to approximately 10.5 years]
- Change From Baseline in Bilirubin [Up to approximately 10.5 years]
- Change From Baseline in Lactate Dehydrogenase (LDH) [Up to approximately 10.5 years]
- Change From Baseline in Haptoglobin [Up to approximately 10.5 years]
- Change From Baseline in Nucleated Red Blood Cells (NRBCs) [Up to approximately 10.5 years]
- Change From Baseline in Erythropoietin (EPO) [Up to approximately 10.5 years]
- Change From Baseline in Soluble Transferrin Receptor [Up to approximately 10.5 years]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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
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.- AG348-C-010
- 2018-002217-35
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
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. |
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)
|
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%
|
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%
|
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 |
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)
|
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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)
|
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)
|
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)
|
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)
|
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
|
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
|
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)
|
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
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 |
medinfo@agios.com |
- AG348-C-010
- 2018-002217-35