A Study to Determine the Efficacy, Safety, Pharmacokineti... | NCT03692052

ID	Type	Description	Link
2018-002217-35	EudraCT Number

Label	Type	Description	Intervention Names
AG-348	Experimental	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

Name	Type	Description	Arm Group Labels	Other Names
AG-348	Drug	AG-348 tablet orally BID	AG-348	Mitapivat

Measure	Description	Time Frame
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.	Up to 12 weeks

Measure	Description	Time Frame
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.	Baseline, Week 12 to Week 24
Percentage of Participants Achieving a Sustained Hb Response (sHR)

Eligibility Module

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).

Name	Affiliation	Role
Medical Affairs	Agios Pharmaceuticals, Inc.	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
UCSF Benioff Children's Hospital Oakland		Oakland	California	94609	United States
Massachusetts General Hospital

PubMed Identifier	Type	Citation	Retractions
35964609	Derived	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.

ID	Title	Description
FG000	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.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Aug 26, 2020	Oct 15, 2021

ID	Title	Description
BG000	AG-348	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.

Units	Counts
Participants	BG00020

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

FAS included all participants who received at least 1 dose of study treatment.

Posted

Number

90% Confidence Interval

percentage of participants

Up to 12 weeks

ID	Title	Description
OG000	AG-348	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.

Units	Counts
Participants	OG00020

Title

Denominators

Categories

Title	Measurements
	OG00080.0(59.90 to 92.86)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000		Clopper-Pearson Method	Significance of p-value associated with the test of H0:Hb response rate =0.3 vs H1:Hb response rate > 0.3.	<.0001														Other

Secondary

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.

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.

Posted

Mean

Standard Deviation

grams per liter (g/L)

Baseline, Week 12 to Week 24

ID	Title	Description
OG000	AG-348	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.

Units	Counts
Participants	OG000

Secondary

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.

FAS included all participants who received at least 1 dose of study treatment.

Posted

Number

90% Confidence Interval

percentage of participants

Week 12 to Week 24

ID	Title	Description
OG000	AG-348	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.

Units	Counts
Participants	OG000

Secondary

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.

FAS included all participants who received at least 1 dose of study treatment.

Posted

Number

90% Confidence Interval

percentage of participants

Week 12 to Week 24

ID	Title	Description
OG000	AG-348	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.

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Hb Concentration Over the Duration of the Extension Period

Not Posted

Sep 2031

Baseline up to approximately 10.5 years

Participants

Secondary

Time to First ≥1.0 g/dL Increase in Hb Concentration

Full Analysis Set (FAS) included all participants who received at least 1 dose of study treatment. Data is reported for the responders.

Posted

Mean

Standard Deviation

weeks

Up to Week 24

ID	Title	Description
OG000	AG-348	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.

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Reticulocyte Count

Not Posted

Sep 2031