A Study to Evaluate the Efficacy and Safety of Mitapivat in Pediatric Participants With Pyruvate Kinase Deficiency (PKD) Who Are Regularly Transfused, Followed by a 5-Year Extension Period

NCT ID: NCT05144256

Last Updated: 2025-12-30

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 49 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-06-08
• Study Completion Date: 2029-06-30

Brief Summary

ACTIVATE-KidsT (AG348-C-022) is a multicenter study designed to evaluate the efficacy and safety of treatment with mitapivat compared with placebo in pediatric participants with pyruvate kinase deficiency (PK deficiency) who are regularly receiving blood transfusions. Participants will be randomized 2:1 to receive either mitapivat or matching placebo. Randomization will be stratified by age (1 to < 6 years, 6 to < 12 years, 12 to < 18 years) and splenectomy status. Participants will be dosed by age and weight during a double-blind period consisting of an 8-week dose titration period followed by a 24-week fixed-dose period. Participants who complete the double-blind period will be eligible to receive mitapivat in the open-label extension (OLE) period.

Conditions

Pediatric Pyruvate Kinase Deficiency; Pediatric Hemolytic Anemia

Keywords

Anemia; Hematologic Diseases; Metabolic Diseases; Mitapivat; AG-348; ACTIVATE-KidsT; PK Deficiency

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Mitapivat

For participants randomized to receive mitapivat, dosing occurs orally twice daily (BID), and is based on age and weight. Dosing is optimized through 2 potential sequential increases in dose levels (1-5 mg, 4-20 mg and 10-50 mg) at Week 4 and Week 8, and aims to achieve the adult-equivalent exposure at 5, 20, and 50 mg. Following titration, participants remain on their individually optimized dose during the remainder of the Double-blind (DB) Period for 24 weeks. After the DB period, participants will enter an Open-label Extension (OLE) Period. To preserve blinding of treatment allocation, participants will continue mitapivat at their optimized dose and undergo mock titration with placebo for 8 weeks. At the conclusion of 8 weeks, participants may continue receiving mitapivat in the OLE Period for up to 262 weeks (including up to 2 weeks of dose taper).

Group Type: EXPERIMENTAL

Mitapivat

Intervention Type: DRUG

Tablets or granules

Mitapivat-matching placebo

Intervention Type: DRUG

Tablets or granules

Placebo

For participants randomized to receive matched placebo, dosing is identical to that described above for mitapivat. Following the initial dose titration period, participants remain on their individually optimized dose during the remainder of the DB period for 32 weeks. After the DB period, participants will enter an OLE period. To preserve blinding of treatment allocation, participants will continue placebo at their optimized dose and undergo mitapivat dose optimization through 2 potential sequential increases in dose levels (1-5 mg, 4-20 mg and 10-50 mg) at Week 4 and Week 8 of the OLE Period, and aims to achieve the adult-equivalent exposure at 5, 20, and 50 mg. At the conclusion of 8 weeks, participants may continue receiving mitapivat in the OLE Period for up to 262 weeks (including up to 2 weeks of dose taper).

Group Type: PLACEBO_COMPARATOR

Mitapivat

Intervention Type: DRUG

Tablets or granules

Mitapivat-matching placebo

Intervention Type: DRUG

Tablets or granules

Interventions

Mitapivat

Tablets or granules

Intervention Type: DRUG

Mitapivat-matching placebo

Tablets or granules

Intervention Type: DRUG

Other Intervention Names

AG-348; AG-348 sulfate hydrate; Mitapivat sulfate

Eligibility Criteria

Inclusion Criteria

• Written informed consent from the participant, or the participant's legally authorized representative, parent(s), or legal guardian, and the participant's assent, where applicable (informed consent/assent) must be obtained before any study-related procedures are conducted, and participants must be willing to comply with all study procedures for the duration of the study;
• Aged 1 to <18 years. Participants between 12 and 24 months of age must weigh a minimum of 7 kilograms (kg);
• Clinical laboratory confirmation of pyruvate kinase deficiency (PKD), defined as documented presence of at least 2 mutant alleles in the pyruvate kinase L/R (PKLR) gene, of which at least 1 is a missense mutation, as determined per the genotyping performed by the study central genotyping laboratory;
• Six to 26 transfusion episodes in the 52-week period before providing informed consent/assent;
• Have complete records of transfusion history for the 52 weeks before providing informed consent/assent, defined as having all the following available: (1) all the transfusion dates, (2) the RBC transfusion volume (milliliters and/or number of units) for all the transfusions, and (3) hemoglobin concentrations within 1 week before transfusion for at least 80% of the transfusions;
• Receiving folic acid supplementation as part of routine clinical care for at least 21 days before administration of the first dose of study drug, to be continued during study participation;
• Female participants who have attained menarche and/or breast development in Tanner Stage 2 must be abstinent of sexual activities that may induce pregnancy 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 informed consent/assent, throughout the study, and for 28 days after the last dose of study drug (including the time required to dose taper). The second form of contraception can include an acceptable barrier method.

Exclusion Criteria

• Pregnant or breastfeeding;
• Homozygous for the R479H mutation or have 2 nonmissense mutations, without the presence of another missense mutation, in the PKLR gene as determined per the genotyping performed by the study central genotyping laboratory;
• History of malignancy;
• History of active and/or uncontrolled cardiac or pulmonary disease or clinically relevant QT prolongation within 6 months before providing informed consent/assent;
• Hepatobiliary disorders including, but not limited to:

• Liver disease with histopathological evidence of cirrhosis or severe fibrosis;
• Clinically symptomatic cholelithiasis or cholecystitis (participants with prior cholecystectomy are eligible);
• History of drug-induced cholestatic hepatitis;
• Aspartate aminotransferase >2.5×upper limit of normal (ULN) (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5×ULN (unless due to hepatic iron deposition);
• Renal dysfunction as defined by an estimated glomerular filtration rate <60 milliliters per minute (mL/min)/1.73 m^2;
• Nonfasting triglycerides >440 milligrams per deciliter (mg/dL) (5 millimoles per liter [mmol/L]);
• Active uncontrolled infection requiring systemic antimicrobial therapy;
• Participants with known active hepatitis B or hepatitis C virus infection;
• Participants with known human immunodeficiency virus (HIV) infection;
• History of major surgery (including splenectomy) ≤6 months before providing informed consent/assent and/or planning on undergoing a major surgical procedure during the screening or double-blind period;
• Current enrollment or past participation (within 90 days before the first dose of study drug or a time frame equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational study drug or device;
• Prior exposure to gene therapy, or bone marrow or stem cell transplantation;
• Currently receiving hematopoietic stimulating agents; the last dose must have been administered at least 28 days or a time frame equivalent to 5 half-lives (whichever is longer) before randomization;
• Receiving products that are strong inhibitors of CYP3A4/5 that have not been stopped for ≥5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong inducers of CYP3A4 that have not been stopped for ≥28 days or a time frame equivalent to 5 half-lives (whichever is longer), before randomization;
• Receiving anabolic steroids, including testosterone preparations, that have not been stopped for at least 28 days before randomization;
• Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, Opadry® II Blue [hypromellose, titanium dioxide, lactose monohydrate, triacetin, and Food, Drug, and Cosmetics blue dye number 2 (FD&C Blue #2)], Opadry® II White [hypromellose, titanium dioxide, lactose monohydrate, and triacetin], and magnesium stearate);
• Any medical, hematologic, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data; also included are:

• Participants who are institutionalized by regulatory or court order.
• Participants with any condition(s) that could create undue influence (including but not limited to incarceration, involuntary psychiatric confinement, and financial or familial affiliation with the Investigator or Sponsor).
• Receiving a pyruvate kinase activator that has not been stopped for ≥52 weeks before providing informed consent/assent.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Agios Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Affairs

Role: STUDY_CHAIR

Agios Pharmaceuticals, Inc.

Locations

Phoenix Children's Hospital

Phoenix, Arizona, United States

Stanford Medicine

Palo Alto, California, United States

Children's Healthcare of Atlanta - Emory

Atlanta, Georgia, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Cure 4 the Kids Foundation, A Division of Roseman University of Health Sciences

Las Vegas, Nevada, United States

Weill Cornell Medical College

New York, New York, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

UT Southwestern Medical Center

Dallas, Texas, United States

Texas Children's Hospital

Houston, Texas, United States

Comprehensive Hemophilia Care Clinic at CHEO (Children's Hospital Eastern Ontario)

Ottawa, Ontario, Canada

Fakultní Nemocnice Olomouc

Olomouc, , Czechia

Aarhus University Hospital

Aarhus, Central Jutland, Denmark

Rigshospitalet

Copenhagen, , Denmark

Charite - UB - CVK - Medizinische Klinik

Berlin, , Germany

Universitair Medisch Centrum Utrecht

Utrecht, , Netherlands

Hospital Universitario Vall d'Hebron

Barcelona, , Spain

Hospital Clinico Universitario Virgen de la Arrixaca

Madrid, , Spain

CHUV University Hospital of Lausanne

Lausanne, Canton of Bern, Switzerland

Ege University Faculty of Medicine

Izmir, Adana, Turkey (Türkiye)

Hacettepe University

Ankara, , Turkey (Türkiye)

İstanbul Üniversitesi Tıp Fakültesi [Istanbul University Faculty of Medicine] Çocuk Sağlığı Enstitüsü [Institute of Child Health]

Istanbul, , Turkey (Türkiye)

King's College Hospital NHS

London, , United Kingdom

Countries

United States; Canada; Czechia; Denmark; Germany; Netherlands; Spain; Switzerland; Turkey (Türkiye); United Kingdom

Other Identifiers

2021-003265-36

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2024-515024-37-00

Identifier Type: CTIS

Identifier Source: secondary_id

AG348-C-022

Identifier Type: -

Identifier Source: org_study_id