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

NCT05144256 | Active Not Recruiting Phase 3 DMC FDA Drug

• 3 other identifiers: AG348-C-0222021-003265-362024-515024-37-00
• Study Type: interventional
• Target: 49
• Locations: 10 countries
• Sites: 22

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

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants Achieving Transfusion Reduction Response (TRR)

  TRR is defined as ≥33% reduction in total red blood cell (RBC) transfusion volume from Week 9 through Week 32 of the double-blind period, normalized by weight and actual study drug duration compared with the historical transfusion volume, standardized by weight, and to 24 weeks.

  Week 9 to Week 32

Secondary Outcomes (26)

• Percentage of Participants With Transfusion-free Response

  Week 9 to Week 32

• Change in the Number of Transfusion Episodes

  Week 9 to Week 32

• Percentage Change in Weight-normalized and Study Treatment Duration-normalized Total Transfusion Volume

  Week 9 to Week 32

• Percentage of Participants With Normal Hemoglobin (Hb) Response

  Week 9 to Week 32

• Change From Baseline in Estradiol Concentration

  Baseline up to Week 298

Study Arms (2)

Mitapivat

EXPERIMENTAL

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).

Drug: Mitapivat; Drug: Mitapivat-matching placebo

Placebo

PLACEBO COMPARATOR

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).

Drug: Mitapivat; Drug: Mitapivat-matching placebo

Interventions

Mitapivat DRUG

Tablets or granules

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

Mitapivat; Placebo

Mitapivat-matching placebo DRUG

Tablets or granules

Mitapivat; 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;
• 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.

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 (22)

Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

Location

Stanford Medicine

Palo Alto, California, 94304, United States

Location

Children's Healthcare of Atlanta - Emory

Atlanta, Georgia, 30322, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

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

Las Vegas, Nevada, 89135, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

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

Ottawa, Ontario, K1H 5B2, Canada

Location

Fakultní Nemocnice Olomouc

Olomouc, 779 00, Czechia

Location

Aarhus University Hospital

Aarhus, Central Jutland, 8200, Denmark

Location

Rigshospitalet

Copenhagen, 2100, Denmark

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 Clinico Universitario Virgen de la Arrixaca

Madrid, 30120, Spain

Location

CHUV University Hospital of Lausanne

Lausanne, Canton of Bern, Switzerland

Location

Ege University Faculty of Medicine

Izmir, Adana, Turkey (Türkiye)

Location

Hacettepe University

Ankara, Turkey (Türkiye)

Location

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

Istanbul, 34093, Turkey (Türkiye)

Location

King's College Hospital NHS

London, SE5 9RS, United Kingdom

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: December 3, 2021
• Study Start: June 8, 2022
• Primary Completion: May 3, 2024
• Study Completion (Estimated): June 1, 2029
• Last Updated: April 24, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1); US (9); DK (2); CH (1); NL (1); CZ (1); ES (2); TU (3); CA (1); DE (1)