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Een studie om de werkzaamheid en veiligheid van Mitapivat te evalueren bij pediatrische deelnemers met pyruvaatkinasedeficiëntie (PKD) die regelmatig een transfusie krijgen, gevolgd door een verlengingsperiode van 5 jaar (ACTIVATE-KidsT)

27 oktober 2026 bijgewerkt door: Agios Pharmaceuticals, Inc.

Een multicenter, gerandomiseerde, dubbelblinde, placebogecontroleerde fase 3-studie ter evaluatie van de werkzaamheid en veiligheid van Mitapivat bij pediatrische proefpersonen met pyruvaatkinasedeficiëntie die regelmatig een transfusie krijgen, gevolgd door een open-label verlengingsperiode van 5 jaar

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.

Studie Overzicht

Toestand

Actief, niet wervend

Conditie

Interventie / Behandeling

Studietype

Ingrijpend

Inschrijving (Werkelijk)

49

Fase

  • Fase 3

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studie Locaties

  • Canada
    • Ontario
      • Ottawa, Ontario, Canada, K1H 5B2
        • Comprehensive Hemophilia Care Clinic at CHEO (Children's Hospital Eastern Ontario)
  • Denemarken
      • Copenhagen, Denemarken, 2100
        • Rigshospitalet
    • Central Jutland
      • Aarhus, Central Jutland, Denemarken, 8200
        • Aarhus University Hospital
  • Duitsland
      • Berlin, Duitsland, 13353
        • Charite - UB - CVK - Medizinische Klinik
  • Nederland
      • Utrecht, Nederland, 3584 CX
        • Universitair Medisch Centrum Utrecht
  • Spanje
      • Barcelona, Spanje, 08035
        • Hospital Universitario Vall d'Hebron
      • Madrid, Spanje, 30120
        • Hospital Clinico Universitario Virgen de la Arrixaca
  • Tsjechië
      • Olomouc, Tsjechië, 779 00
        • Fakultní Nemocnice Olomouc
  • Turkije (Türkiye)
      • Ankara, Turkije (Türkiye)
        • Hacettepe University
      • Istanbul, Turkije (Türkiye), 34093
        • İstanbul Üniversitesi Tıp Fakültesi [Istanbul University Faculty of Medicine] Çocuk Sağlığı Enstitüsü [Institute of Child Health]
    • Adana
      • Izmir, Adana, Turkije (Türkiye)
        • Ege University Faculty of Medicine
  • Verenigd Koninkrijk
      • London, Verenigd Koninkrijk, SE5 9RS
        • King's College Hospital NHS
  • Verenigde Staten
    • Arizona
      • Phoenix, Arizona, Verenigde Staten, 85016
        • Phoenix Children's Hospital
    • California
      • Palo Alto, California, Verenigde Staten, 94304
        • Stanford Medicine
    • Georgia
      • Atlanta, Georgia, Verenigde Staten, 30322
        • Children's Healthcare of Atlanta - Emory
    • Massachusetts
      • Boston, Massachusetts, Verenigde Staten, 02115
        • Boston Children's Hospital
    • Nevada
      • Las Vegas, Nevada, Verenigde Staten, 89135
        • Cure 4 the Kids Foundation, A Division of Roseman University of Health Sciences
    • New York
      • New York, New York, Verenigde Staten, 10065
        • Weill Cornell Medical College
    • Pennsylvania
      • Philadelphia, Pennsylvania, Verenigde Staten, 19104
        • Children's Hospital of Philadelphia
    • Texas
      • Dallas, Texas, Verenigde Staten, 75390
        • UT Southwestern Medical Center
      • Houston, Texas, Verenigde Staten, 77030
        • Texas Children's Hospital
  • Zwitserland
    • Canton of Bern
      • Lausanne, Canton of Bern, Zwitserland
        • CHUV University Hospital of Lausanne

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

1 jaar tot 17 jaar (Kind)

Accepteert gezonde vrijwilligers

Nee

Geslachten die in aanmerking komen voor studie

Allemaal

Beschrijving

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.

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

  • Primair doel: Behandeling
  • Toewijzing: Gerandomiseerd
  • Interventioneel model: Parallelle opdracht
  • Masker: Verviervoudigen

Wapens en interventies

Deelnemersgroep / Arm
Interventie / Behandeling
Experimenteel: 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).
Geneesmiddel: Mitapivat

Tablets or granules

Andere namen:
  • AG-348
  • AG-348 sulfaathydraat
  • Mitapivat sulfaat
Geneesmiddel: Mitapivat-matching placebo

Tablets or granules
Placebo-vergelijker: 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).
Geneesmiddel: Mitapivat

Tablets or granules

Andere namen:
  • AG-348
  • AG-348 sulfaathydraat
  • Mitapivat sulfaat
Geneesmiddel: Mitapivat-matching placebo

Tablets or granules

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Percentage of Participants Achieving Transfusion Reduction Response (TRR)
Tijdsspanne: Week 9 to Week 32

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

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Populatie Farmacokinetisch (PK) Model Parameter Schatting: Maximale plasmaconcentratie (Cmax) van Mitapivat
Tijdsspanne: Week 2, 8, 12 en 16
Week 2, 8, 12 en 16
Populatie PK-model Parameterschatting: oppervlakte onder de concentratie-tijdcurve (AUC) afgeleid van plasmaconcentraties van Mitapivat
Tijdsspanne: Week 2, 8, 12 en 16
Week 2, 8, 12 en 16
Concentratie bij Steady State (Css) van Mitapivat
Tijdsspanne: Week 16: 6 en 8 uur na de dosis
Week 16: 6 en 8 uur na de dosis
Trogconcentratie (Ctrough) van Mitapivat
Tijdsspanne: Week 8: ≤30 minuten voordosering; Week 12: ≤30 minuten voordosering
Week 8: ≤30 minuten voordosering; Week 12: ≤30 minuten voordosering
Verandering van basislijn in oestradiolconcentratie
Tijdsspanne: Basislijn tot week 298
Basislijn tot week 298
Verandering van basislijn in oestronconcentratie
Tijdsspanne: Basislijn tot week 298
Basislijn tot week 298
Verandering van basislijn in totale testosteronconcentratie
Tijdsspanne: Basislijn tot week 298
Basislijn tot week 298
Verandering ten opzichte van de uitgangswaarde in vrije testosteronconcentratie bij deelnemers ≥ 7 jaar of leerlooierstadium ≥ 2 (afhankelijk van wat zich het eerst voordoet)
Tijdsspanne: Basislijn tot week 298
Basislijn tot week 298
Verandering ten opzichte van baseline in luteïniserend hormoonconcentratie bij deelnemers ≥6 jaar
Tijdsspanne: Basislijn tot week 298
Basislijn tot week 298
Percentage aantal vrouwelijke deelnemers met ontwikkeling van ovariumcysten
Tijdsspanne: Basislijn tot week 298
Basislijn tot week 298
Verandering ten opzichte van de uitgangswaarde in de grootte van ovariumcysten bij vrouwelijke deelnemers
Tijdsspanne: Basislijn tot week 298
Basislijn tot week 298
Wijziging vanaf basislijn in lengte-voor-leeftijd Z-score
Tijdsspanne: Basislijn tot week 298
Basislijn tot week 298
Verandering ten opzichte van baseline in Z-score voor gewicht voor leeftijd
Tijdsspanne: Basislijn tot week 298
Basislijn tot week 298
Verandering vanaf baseline in Body Mass Index (BMI)-voor-leeftijd Z-score
Tijdsspanne: Basislijn tot week 298
Basislijn tot week 298
Verandering ten opzichte van baseline in Bone Mineral Density (BMD) Z-score
Tijdsspanne: Basislijn tot week 298
Basislijn tot week 298
Wijziging ten opzichte van baseline in serumijzerconcentratie
Tijdsspanne: Basislijn tot week 292
Basislijn tot week 292
Wijziging ten opzichte van de basislijn in serumferritineconcentratie
Tijdsspanne: Basislijn tot week 292
Basislijn tot week 292
Verandering ten opzichte van baseline in totale ijzerbindende capaciteit
Tijdsspanne: Basislijn tot week 292
Basislijn tot week 292
Wijziging ten opzichte van baseline in transferrine/transferrineverzadiging
Tijdsspanne: Basislijn tot week 292
Basislijn tot week 292
Percentage of Participants With Transfusion-free Response
Tijdsspanne: Week 9 to Week 32

Transfusion-free response is defined as achievement of 0 transfusions administered from Week 9 through Week 32 of the double-blind period.
Week 9 to Week 32
Change in the Number of Transfusion Episodes
Tijdsspanne: Week 9 to Week 32

The change in the number of transfusion episodes from Week 9 through Week 32 of the double-blind period compared with the historical number of transfusion episodes standardized to 24 weeks.
Week 9 to Week 32
Percentage Change in Weight-normalized and Study Treatment Duration-normalized Total Transfusion Volume
Tijdsspanne: Week 9 to Week 32

The percentage change in weight-normalized and study treatment duration-normalized total transfusion volume from Week 9 through Week 32 of the double-blind period will be compared with the historical transfusion volume standardized by weight and to 24 weeks.
Week 9 to Week 32
Percentage of Participants With Normal Hemoglobin (Hb) Response
Tijdsspanne: Week 9 to Week 32

Normal Hb response is defined as achievement of Hb concentrations in the normal range at least once, 8 weeks or more after a transfusion during Week 9 through Week 32 of the double-blind period.
Week 9 to Week 32
Change From Baseline in Sexual Maturity Rating with Tanner Stage
Tijdsspanne: Baseline up to Week 298

Tanner Stage 1 corresponds to the prepubertal form, with progression to Tanner Stage 5, the final adult form.
Baseline up to Week 298
Change from Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale
Tijdsspanne: Baseline up to Week 292

The PedsQL multidimensional fatigue scale yields a total score from age-appropriate validated questionnaire that asks for perceived fatigue within the domains of 'General', 'Sleep/Rest' and 'Cognitive'. Each domain consists of 6 questions that are rated from 0 to 4 (therefore total score can range from 0 to 72). A higher total score indicates greater fatigue (i.e., worse outcome).
Baseline up to Week 292
Change from Baseline in PedsQL Generic Core Scale (GCS)
Tijdsspanne: Baseline up to Week 292

PedsQL GCS is designed to measure health-related quality of life in pediatric participants and adolescents (2 to 18 years of age). It encompasses 4 dimensions of functioning (physical [8 items], emotional [5 items], social [5 items], school [3 items]). Age groups: Toddler (2-4 years), Young pediatric (5-7 years), Pediatric (8-12 years), and Teens (13-17 years). Depending on the participant's age, the questionnaire may be completed by parent/caregiver as appropriate. For the Toddler group, the PedsQL GCS consist of 21 items, using a 5-point Likert scale (0 to 4); for all other groups, the PedsQL GCS consist of 23 items, with a 3-point Likert scale (0, 2, 4) for the young pediatric, and a 5-point Likert scale for the pediatric and teens groups. Scores are transformed on a scale from 0 to 100 where 0=100, 1=75, 2=50, 3=25, and 4=0. Higher scores indicate improved quality of life.
Baseline up to Week 292

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Agios Pharmaceuticals, Inc.

Onderzoekers

  • Studie stoel: Medical Affairs, Agios Pharmaceuticals, Inc.

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Werkelijk)

8 juni 2022

Primaire voltooiing (Werkelijk)

3 mei 2024

Studie voltooiing (Geschat)

1 juni 2029

Studieregistratiedata

Eerst ingediend

22 november 2021

Eerst ingediend dat voldeed aan de QC-criteria

22 november 2021

Eerst geplaatst (Werkelijk)

3 december 2021

Updates van studierecords

Laatste update geplaatst (Werkelijk)

28 oktober 2026

Laatste update ingediend die voldeed aan QC-criteria

27 oktober 2026

Laatst geverifieerd

1 oktober 2026

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

  • AG348-C-022
  • 2021-003265-36 (EudraCT-nummer)
  • 2024-515024-37-00 (Ctis)

Plan Individuele Deelnemersgegevens (IPD)

Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?

NEE

Informatie over medicijnen en apparaten, studiedocumenten

Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel

Ja

Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

Nee

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