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A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)

Primary Purpose

Pyruvate Kinase Deficiency, Anemia, Hemolytic

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Placebo
AG-348
Sponsored by
Agios Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pyruvate Kinase Deficiency

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Informed consent;
  • Male or female, aged 18 years or older;
  • Documented clinical laboratory confirmation of pyruvate kinase (PK) deficiency, defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation;
  • Hemoglobin (Hb) concentration less than or equal to 10.0 grams per deciliter (g/dL) regardless of gender (average of at least 2 Hb measurements [separated by a minimum of 7 days] during the Screening Period)
  • Considered not regularly transfused, defined as having had no more than 4 transfusion episodes in the 12-month period up to the first day of study treatment and no transfusions in the 3 months prior to the first day of study treatment;
  • Received at least 0.8 mg oral folic acid daily for at least 21 days prior to the first dose of study treatment, to be continued daily during study participation.
  • Adequate organ function;
  • Women of reproductive potential, have a negative serum pregnancy test;
  • 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 agree 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 treatment for women and 90 days for men following the last dose of study treatment;
  • Willing to comply with all study procedures for the duration of the study;

Exclusion Criteria:

  • Homozygous for the R479H mutation or have 2 non-missense mutations, without the presence of another missense mutation, in the PKLR gene;
  • Significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound the interpretation of the study data;
  • Splenectomy scheduled during the study treatment period or have 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. Prior and subsequent participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted however, concurrent participation is not; participants enrolling in this current study will be expected to temporarily suspend participation in the NHS or Registry;
  • Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study treatment;
  • Prior treatment with a pyruvate kinase activator;
  • 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 dose of study treatment;
  • Currently receiving hematopoietic stimulating agents that have not been stopped for a duration of at least 28 days prior to the first dose of study treatment;
  • 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;
  • Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to treatment.

Sites / Locations

  • University of Arkansas for Medical Sciences
  • Emory University
  • Indiana Hemophilia and Thrombosis Center
  • Massachusetts General Hospital
  • The Children's Hospital Corporation d/b/a Boston's Children Hospital
  • Wayne State University School of Medicine, Children's Hospital of Michigan
  • Duke University
  • East Carolina University
  • Cincinnati Children's Hospital Medical Center
  • Houston Methodist Research Institute
  • Primary Children's Hospital Univ. of Utah
  • Seattle Cancer Care Alliance
  • Hospital Central da Faculdade de Medicina USP Cidade Universitaria
  • McMaster University - Health Sciences Centre
  • Toronto General Hospital, University Health Network
  • Institute of Hematology and Blood Transfusion
  • University of Copenhagen, Herlev Hospital
  • CHU Amiens Picardie
  • Hopital Saint-Andre
  • Hôpital Henri-Mondor
  • Hôpital de la Timone
  • Institut Claudius Regaud
  • Charite University Medicine
  • Universitätsklinikum Würzburg
  • Ospedale Galliera
  • Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
  • AOU Policlinico, Università della Campania "Luigi Vanvitelli"
  • Tohoku University Hospital
  • Kyoto Katsura Hospital
  • Agios Investigative Site
  • Osaka City General Hospital
  • Kansai Medical University, Department of Pediatrics, Hirakata Hospital
  • Toho University Omori Medical Center
  • Yeungnam University Hospital
  • Universitair Medisch Centrum Utrecht
  • Hospital U. Vall d'Hebron Servicio de Hematología Clínica
  • Hospital Clinico Universitario Virgen de la Arricaxa
  • Hospital Universitario La Paz
  • Centre Hospitalier Universitaire Vaudois (CHUV)
  • Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj
  • Hacettepe University
  • Addenbrooke's Hospital
  • The Royal Liverpool and Broadgreen University
  • Imperial College Healthcare NHS Trust, Hammersmith Hospital
  • University College London
  • Manchester Royal Infirmary

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Experimental

Experimental

Experimental

Arm Label

Placebo

AG-348, 5 mg

AG-348, 20 mg

AG-348, 50 mg

Arm Description

Participants received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.

Participants received AG-348 tablets, 5 milligrams (mg) twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.

Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.

Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.

Outcomes

Primary Outcome Measures

Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR)
Hemoglobin response (HR) is defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24. The baseline Hb concentration is the average of all available Hb concentrations for a participant during the Screening Period up to the first dose of study treatment. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).

Secondary Outcome Measures

Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24
This is the change in Hb concentration at Weeks 16, 20 and 24 compared to baseline. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Maximum Change From Baseline in Hb Concentration
This is the maximum change from baseline in Hb concentration up to Week 24. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More
This is the time taken to first achieve an increase of hemoglobin concentration of 1.5 g/dL or more from baseline. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24
The change from baseline in indirect bilirubin levels was summarized. Indirect bilirubin is a marker for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24
The change from baseline in LDH levels was summarized. LDH is a marker for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24
The change from baseline in haptoglobin levels was summarized. Haptoglobin levels are markers for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24
The change from baseline in reticulocyte percentage was summarized. Reticulocyte levels are markers for hematopoietic activity. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24
The PKDD is a 7-item patient reported outcome (PRO) measure of the core signs and symptoms associated with PK deficiency in adults. Participants rate their experience with symptoms of PK deficiency on the present day. The symptoms include those associated with tiredness, jaundice, bone pain, shortness of breath, and energy level. The score ranges from 25 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDD weekly scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24
The PKDIA is a 12-item patient reported outcome (PRO) measure of the common impacts of PK deficiency on activities of daily living. Participants rate how PK deficiency has impacted aspects of daily living in the past 7 days, including impacts on relationships; perceived appearance; work performance; and leisure, social, mental, and physical activities. The score range is 30 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDIA scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Percentage of Participants With Adverse Events
An AE is any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12
Maximum Plasma Concentration (Cmax) for AG-348
Time to Cmax (Tmax) for AG-348
Time to Last Measurable Concentration (Tlast) for AG-348
Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
Predicted probability of experiencing all grade hot flush at the doses of 5, 20, and 50 mg mitapivat BID based on exposure-response model.
Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
Predicted percent change from baseline at Week 24 in the sex hormone measures (total testosterone, free testosterone, and estrone) at the doses of 5, 20, and 50 mg mitapivat BID in male participants.

Full Information

First Posted
May 24, 2018
Last Updated
May 20, 2022
Sponsor
Agios Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03548220
Brief Title
A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
Official Title
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Subjects With Pyruvate Kinase Deficiency
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Completed
Study Start Date
August 9, 2018 (Actual)
Primary Completion Date
October 9, 2020 (Actual)
Study Completion Date
October 9, 2020 (Actual)

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
Yes

5. Study Description

Brief Summary
Study AG348-C-006 evaluated the efficacy and safety of orally administered AG-348 as compared with placebo in participants with pyruvate kinase (PK) deficiency, who were not regularly receiving blood transfusions. Participants were randomized 1:1 to receive either AG-348 or a matching placebo.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pyruvate Kinase Deficiency, Anemia, Hemolytic

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
80 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Participants received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.
Arm Title
AG-348, 5 mg
Arm Type
Experimental
Arm Description
Participants received AG-348 tablets, 5 milligrams (mg) twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Arm Title
AG-348, 20 mg
Arm Type
Experimental
Arm Description
Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Arm Title
AG-348, 50 mg
Arm Type
Experimental
Arm Description
Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo matching AG-348 tablets, administered to maintain the blind.
Intervention Type
Drug
Intervention Name(s)
AG-348
Intervention Description
AG-348 tablets.
Primary Outcome Measure Information:
Title
Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR)
Description
Hemoglobin response (HR) is defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24. The baseline Hb concentration is the average of all available Hb concentrations for a participant during the Screening Period up to the first dose of study treatment. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time Frame
Baseline, Weeks 16, 20, 24
Secondary Outcome Measure Information:
Title
Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24
Description
This is the change in Hb concentration at Weeks 16, 20 and 24 compared to baseline. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time Frame
Baseline, Weeks 16, 20, 24
Title
Maximum Change From Baseline in Hb Concentration
Description
This is the maximum change from baseline in Hb concentration up to Week 24. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time Frame
Baseline, up to Week 24
Title
Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More
Description
This is the time taken to first achieve an increase of hemoglobin concentration of 1.5 g/dL or more from baseline. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time Frame
Baseline, up to Week 24
Title
Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24
Description
The change from baseline in indirect bilirubin levels was summarized. Indirect bilirubin is a marker for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time Frame
Baseline, Weeks 16, 20, 24
Title
Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24
Description
The change from baseline in LDH levels was summarized. LDH is a marker for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time Frame
Baseline, Weeks 16, 20, 24
Title
Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24
Description
The change from baseline in haptoglobin levels was summarized. Haptoglobin levels are markers for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time Frame
Baseline, Weeks 16, 20, 24
Title
Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24
Description
The change from baseline in reticulocyte percentage was summarized. Reticulocyte levels are markers for hematopoietic activity. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time Frame
Baseline, Weeks 16, 20, 24
Title
Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24
Description
The PKDD is a 7-item patient reported outcome (PRO) measure of the core signs and symptoms associated with PK deficiency in adults. Participants rate their experience with symptoms of PK deficiency on the present day. The symptoms include those associated with tiredness, jaundice, bone pain, shortness of breath, and energy level. The score ranges from 25 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDD weekly scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time Frame
Baseline, Week 24
Title
Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24
Description
The PKDIA is a 12-item patient reported outcome (PRO) measure of the common impacts of PK deficiency on activities of daily living. Participants rate how PK deficiency has impacted aspects of daily living in the past 7 days, including impacts on relationships; perceived appearance; work performance; and leisure, social, mental, and physical activities. The score range is 30 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDIA scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Time Frame
Baseline, Week 24
Title
Percentage of Participants With Adverse Events
Description
An AE is any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Time Frame
From signing of informed consent form to the end of study, including follow-up (up to Day 197)
Title
Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12
Time Frame
Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Title
Maximum Plasma Concentration (Cmax) for AG-348
Time Frame
Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Title
Time to Cmax (Tmax) for AG-348
Time Frame
Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Title
Time to Last Measurable Concentration (Tlast) for AG-348
Time Frame
Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Title
Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
Description
Predicted probability of experiencing all grade hot flush at the doses of 5, 20, and 50 mg mitapivat BID based on exposure-response model.
Time Frame
From first dose of mitapivat to the end of study, including follow-up (up to Day 197)
Title
Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
Description
Predicted percent change from baseline at Week 24 in the sex hormone measures (total testosterone, free testosterone, and estrone) at the doses of 5, 20, and 50 mg mitapivat BID in male participants.
Time Frame
Baseline, Week 24
Other Pre-specified Outcome Measures:
Title
Percentage of Participants With Adverse Events of Special Interest (AESI)
Description
An AE is any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AESI can be serious or non-serious.
Time Frame
Through 4 weeks after last dose (approximately Week 31)
Title
Change From Baseline in Bone Mineral Density Z-Score at Week 24
Time Frame
Baseline, Week 24
Title
Change From Baseline in Bone Mineral Density T-Score at Week 24
Time Frame
Baseline, Week 24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Informed consent; Male or female, aged 18 years or older; Documented clinical laboratory confirmation of pyruvate kinase (PK) deficiency, defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation; Hemoglobin (Hb) concentration less than or equal to 10.0 grams per deciliter (g/dL) regardless of gender (average of at least 2 Hb measurements [separated by a minimum of 7 days] during the Screening Period) Considered not regularly transfused, defined as having had no more than 4 transfusion episodes in the 12-month period up to the first day of study treatment and no transfusions in the 3 months prior to the first day of study treatment; Received at least 0.8 mg oral folic acid daily for at least 21 days prior to the first dose of study treatment, to be continued daily during study participation. Adequate organ function; Women of reproductive potential, have a negative serum pregnancy test; 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 agree 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 treatment for women and 90 days for men following the last dose of study treatment; Willing to comply with all study procedures for the duration of the study; Exclusion Criteria: Homozygous for the R479H mutation or have 2 non-missense mutations, without the presence of another missense mutation, in the PKLR gene; Significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound the interpretation of the study data; Splenectomy scheduled during the study treatment period or have 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. Prior and subsequent participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted however, concurrent participation is not; participants enrolling in this current study will be expected to temporarily suspend participation in the NHS or Registry; Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study treatment; Prior treatment with a pyruvate kinase activator; 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 dose of study treatment; Currently receiving hematopoietic stimulating agents that have not been stopped for a duration of at least 28 days prior to the first dose of study treatment; 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; Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to treatment.
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
University of Arkansas for Medical Sciences
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72205
Country
United States
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Indiana Hemophilia and Thrombosis Center
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46260
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
The Children's Hospital Corporation d/b/a Boston's Children Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Wayne State University School of Medicine, Children's Hospital of Michigan
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48304
Country
United States
Facility Name
Duke University
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
East Carolina University
City
Greenville
State/Province
North Carolina
ZIP/Postal Code
27858
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Houston Methodist Research Institute
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Primary Children's Hospital Univ. of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Facility Name
Seattle Cancer Care Alliance
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
Hospital Central da Faculdade de Medicina USP Cidade Universitaria
City
São Paulo
Country
Brazil
Facility Name
McMaster University - Health Sciences Centre
City
Hamilton
ZIP/Postal Code
L8S 4LB
Country
Canada
Facility Name
Toronto General Hospital, University Health Network
City
Toronto
ZIP/Postal Code
M5G 2C4
Country
Canada
Facility Name
Institute of Hematology and Blood Transfusion
City
Prague
Country
Czechia
Facility Name
University of Copenhagen, Herlev Hospital
City
Herlev
ZIP/Postal Code
2730
Country
Denmark
Facility Name
CHU Amiens Picardie
City
Amiens
ZIP/Postal Code
80054
Country
France
Facility Name
Hopital Saint-Andre
City
Bordeaux
Country
France
Facility Name
Hôpital Henri-Mondor
City
Créteil
ZIP/Postal Code
94010
Country
France
Facility Name
Hôpital de la Timone
City
Marseille, Cedex 5
ZIP/Postal Code
13385
Country
France
Facility Name
Institut Claudius Regaud
City
Toulouse
Country
France
Facility Name
Charite University Medicine
City
Berlin
Country
Germany
Facility Name
Universitätsklinikum Würzburg
City
Würzburg
ZIP/Postal Code
97080
Country
Germany
Facility Name
Ospedale Galliera
City
Genova
ZIP/Postal Code
16128
Country
Italy
Facility Name
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
City
Milano
ZIP/Postal Code
20122
Country
Italy
Facility Name
AOU Policlinico, Università della Campania "Luigi Vanvitelli"
City
Napoli
ZIP/Postal Code
80138
Country
Italy
Facility Name
Tohoku University Hospital
City
Sendai-City
State/Province
Miyagi
Country
Japan
Facility Name
Kyoto Katsura Hospital
City
Kyoto
Country
Japan
Facility Name
Agios Investigative Site
City
Mie
Country
Japan
Facility Name
Osaka City General Hospital
City
Osaka
ZIP/Postal Code
534-0021
Country
Japan
Facility Name
Kansai Medical University, Department of Pediatrics, Hirakata Hospital
City
Osaka
Country
Japan
Facility Name
Toho University Omori Medical Center
City
Tokyo
Country
Japan
Facility Name
Yeungnam University Hospital
City
Daegu 705-703
ZIP/Postal Code
42415
Country
Korea, Republic of
Facility Name
Universitair Medisch Centrum Utrecht
City
Utrecht
ZIP/Postal Code
3584
Country
Netherlands
Facility Name
Hospital U. Vall d'Hebron Servicio de Hematología Clínica
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Hospital Clinico Universitario Virgen de la Arricaxa
City
El Palmar
ZIP/Postal Code
30120
Country
Spain
Facility Name
Hospital Universitario La Paz
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Centre Hospitalier Universitaire Vaudois (CHUV)
City
Lausanne
ZIP/Postal Code
1011
Country
Switzerland
Facility Name
Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj
City
Bangkok
ZIP/Postal Code
10700
Country
Thailand
Facility Name
Hacettepe University
City
Ankara
Country
Turkey
Facility Name
Addenbrooke's Hospital
City
Cambridge
ZIP/Postal Code
94609
Country
United Kingdom
Facility Name
The Royal Liverpool and Broadgreen University
City
Liverpool
ZIP/Postal Code
L7 8XP
Country
United Kingdom
Facility Name
Imperial College Healthcare NHS Trust, Hammersmith Hospital
City
London
ZIP/Postal Code
W12 0NN
Country
United Kingdom
Facility Name
University College London
City
London
ZIP/Postal Code
W12 0NN
Country
United Kingdom
Facility Name
Manchester Royal Infirmary
City
Manchester
ZIP/Postal Code
M13 9WL
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35417638
Citation
Al-Samkari H, Galacteros F, Glenthoj A, Rothman JA, Andres O, Grace RF, Morado-Arias M, Layton DM, Onodera K, Verhovsek M, Barcellini W, Chonat S, Judge MP, Zagadailov E, Xu R, Hawkins P, Beynon V, Gheuens S, van Beers EJ; ACTIVATE Investigators. Mitapivat versus Placebo for Pyruvate Kinase Deficiency. N Engl J Med. 2022 Apr 14;386(15):1432-1442. doi: 10.1056/NEJMoa2116634.
Results Reference
derived
PubMed Identifier
31974203
Citation
Rab MAE, Van Oirschot BA, Kosinski PA, Hixon J, Johnson K, Chubukov V, Dang L, Pasterkamp G, Van Straaten S, Van Solinge WW, Van Beers EJ, Kung C, Van Wijk R. AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes. Haematologica. 2021 Jan 1;106(1):238-249. doi: 10.3324/haematol.2019.238865.
Results Reference
derived

Learn more about this trial

A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)

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