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

NCT05175105 | Active Not Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: AG348-C-0232021-003333-11
• Study Type: interventional
• Target: 30
• Locations: 7 countries
• Sites: 19

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

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants Achieving a Hemoglobin (Hb) Response

  Hb response is defined as a ≥1.5 grams per deciliter (g/dL) (0.93 millimoles per liter \[mmol/L\]) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 12, 16, and 20 during the double-blind period. The individual participant's baseline Hb concentration is defined as the average of all available Hb concentrations collected for that participant during the screening period up to the first dose of study drug.

  Baseline up to Week 20

Secondary Outcomes (28)

• Average Change From Baseline in Hb Concentration at Weeks 12, 16, and 20

  Baseline, Weeks 12, 16, and 20

• Maximal Change in Hb Concentration From Baseline During the Double-blind Period

  Baseline up to Week 20

• Change From Baseline in Estradiol Concentration

  Baseline up to Week 286

• Change From Baseline in Estrone Concentration

  Baseline up to Week 286

• Change From Baseline in Total Testosterone Concentration

  Baseline up to Week 286

Study Arms (3)

Mitapivat

EXPERIMENTAL

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.

Drug: Mitapivat

Placebo

PLACEBO COMPARATOR

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.

Drug: Mitapivat-matching placebo

Mitapivat (OLE period)

EXPERIMENTAL

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).

Drug: Mitapivat; Drug: Mitapivat-matching placebo

Interventions

Mitapivat DRUG

Tablets or granules

Also known as: AG-348, AG-348 sulfate hydrate, Mitapivat sulfate

Mitapivat; Mitapivat (OLE period)

Mitapivat-matching placebo DRUG

Tablets or granules

Mitapivat (OLE period); Placebo

Eligibility Criteria

• Age: 1 Year - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Agios Pharmaceuticals, Inc.: lead

Study Sites (19)

Stanford Medicine

Palo Alto, California, 94304, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's Healthcare of Atlanta - Emory

Atlanta, Georgia, 30322, United States

Location

UChicago Medicine

Chicago, Illinois, 60637, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Children's Hospital of Michigan

Detroit, Michigan, 48304, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

St Jude's Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Centre hospitalier Universitaire de Sainte-Justine

Montreal, Quebec, QC H3T 1C5, Canada

Location

Hôpital Pellegrin

Bordeaux, Aquitaine, 33000, France

Location

Universitatsklinikum Wurzburg

Würzburg, Bavaria, 97080, Germany

Location

Charite - UB - CVK - Medizinische Klinik

Berlin, 13353, Germany

Location

Universitair Medisch Centrum Utrecht

Utrecht, 3584 CX, Netherlands

Location

Hospital Universitario Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario Infantil Nino Jesus

Madrid, 28009, Spain

Location

CHUV University Hospital of Lausanne

Lausanne, Canton of Bern, Switzerland

Location

MeSH Terms

Conditions

Anemia; Hematologic Diseases; Metabolic Diseases; Pyruvate Kinase Deficiency of Red Cells

Interventions

mitapivat

Condition Hierarchy (Ancestors)

Hemic and Lymphatic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Medical Affairs

  Agios Pharmaceuticals, Inc.

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 22, 2021
• First Posted: January 3, 2022
• Study Start: June 6, 2022
• Primary Completion: December 13, 2024
• Study Completion (Estimated): January 1, 2030
• Last Updated: April 24, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

DE (2); US (11); FR (1); CA (1); NL (1); ES (2); CH (1)