A Study to Evaluate the Efficacy and Safety of Mitapivat in Pediatric Participants With Pyruvate Kinase Deficiency (PKD) Who Are Not Regularly Transfused, Followed by a 5-Year Extension Period

NCT ID: NCT05175105

Last Updated: 2025-12-30

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-06-06
• Study Completion Date: 2030-01-31

Brief Summary

Study ACTIVATE-Kids (AG348-C-023) will evaluate the efficacy and safety of orally administered mitapivat as compared with placebo in pediatric participants with pyruvate kinase deficiency (PKD) who are not 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). Participants will be dosed by age and weight during a double-blind period consisting of an 8-week dose titration period followed by a 12-week fixed-dose period. Participants who complete the double-blind period will be eligible to receive mitapivat for up to 5 years 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-Kids; PK Deficiency

Study Design

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

Study Groups

Placebo

Double-Blind Period: Participants will receive mitapivat-matching placebo orally for 8 weeks in the dose titration period and for 12 weeks in the fixed-dose period.

Group Type: PLACEBO_COMPARATOR

Mitapivat-matching placebo

Intervention Type: DRUG

Tablets or granules

Mitapivat

Double-Blind Period: Participants will receive mitapivat orally, at doses based on age and weight, for 8 weeks in the dose titration period and for 12 weeks in the fixed-dose period.

Group Type: EXPERIMENTAL

Mitapivat

Intervention Type: DRUG

Tablets or granules

Mitapivat (OLE period)

Participants who have completed the double-blind period will be eligible to receive mitapivat for up to 5 years in the OLE period. Participants entering the OLE period will first receive blinded mitapivat and placebo for 8 weeks to maintain the double-blind treatment assignment before being transitioned to only receive active, open-label drug (mitapivat).

Group Type: EXPERIMENTAL

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;
• No more than 5 red blood cell (RBC) transfusions in the 52-week period before providing informed consent/assent and no RBC transfusions ≤12 weeks before administration of the first dose of study drug;
• Hemoglobin concentration ≤10 grams per deciliter (g/dL) for participants 12 to <18 years of age or ≤9 g/dL for participants 1 to <12 years of age during the screening period. Hb concentration must be based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the screening period;
• 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

Stanford Medicine

Palo Alto, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Children's Healthcare of Atlanta - Emory

Atlanta, Georgia, United States

UChicago Medicine

Chicago, Illinois, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Children's Hospital of Michigan

Detroit, Michigan, United States

Duke University Medical Center

Durham, North Carolina, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

St Jude's Children's Research Hospital

Memphis, Tennessee, United States

UT Southwestern Medical Center

Dallas, Texas, United States

Texas Children's Hospital

Houston, Texas, United States

Centre hospitalier Universitaire de Sainte-Justine

Montreal, Quebec, Canada

Hôpital Pellegrin

Bordeaux, Aquitaine, France

Universitatsklinikum Wurzburg

Würzburg, Bavaria, Germany

Charite - UB - CVK - Medizinische Klinik

Berlin, , Germany

Universitair Medisch Centrum Utrecht

Utrecht, , Netherlands

Hospital Universitario Vall d'Hebron

Barcelona, , Spain

Hospital Universitario Infantil Nino Jesus

Madrid, , Spain

CHUV University Hospital of Lausanne

Lausanne, Canton of Bern, Switzerland

Countries

Israel; Italy; United States; Canada; France; Germany; Netherlands; Spain; Switzerland

Other Identifiers

2021-003333-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

AG348-C-023

Identifier Type: -

Identifier Source: org_study_id