Un estudio para evaluar la eficacia y la seguridad de Mitapivat en participantes pediátricos con deficiencia de piruvato quinasa (PKD) que reciben transfusiones regulares, seguido de un período de extensión de 5 años (ACTIVATE-KidsT)
Estudio de fase 3, multicéntrico, aleatorizado, doble ciego, controlado con placebo para evaluar la eficacia y la seguridad de mitapivat en sujetos pediátricos con deficiencia de piruvato quinasa que reciben transfusiones regulares, seguido de un período de extensión abierto de 5 años
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.
Descripción general del estudio
Estado
Intervención / Tratamiento
Tipo de estudio
Inscripción (Actual)
Fase
- Fase 3
Contactos y Ubicaciones
Ubicaciones de estudio
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Berlin, Alemania, 13353
- Charite - UB - CVK - Medizinische Klinik
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Ontario
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Ottawa, Ontario, Canadá, K1H 5B2
- Comprehensive Hemophilia Care Clinic at CHEO (Children's Hospital Eastern Ontario)
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Olomouc, Chequia, 779 00
- Fakultní Nemocnice Olomouc
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Copenhagen, Dinamarca, 2100
- Rigshospitalet
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Central Jutland
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Aarhus, Central Jutland, Dinamarca, 8200
- Aarhus University Hospital
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Barcelona, España, 08035
- Hospital Universitario Vall d'Hebron
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Madrid, España, 30120
- Hospital Clinico Universitario Virgen de la Arrixaca
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Arizona
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Phoenix, Arizona, Estados Unidos, 85016
- Phoenix Children's Hospital
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California
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Palo Alto, California, Estados Unidos, 94304
- Stanford Medicine
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Georgia
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Atlanta, Georgia, Estados Unidos, 30322
- Children's Healthcare of Atlanta - Emory
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Massachusetts
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Boston, Massachusetts, Estados Unidos, 02115
- Boston Children's Hospital
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Nevada
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Las Vegas, Nevada, Estados Unidos, 89135
- Cure 4 the Kids Foundation, A Division of Roseman University of Health Sciences
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New York
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New York, New York, Estados Unidos, 10065
- Weill Cornell Medical College
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Pennsylvania
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Philadelphia, Pennsylvania, Estados Unidos, 19104
- Children's Hospital of Philadelphia
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Texas
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Dallas, Texas, Estados Unidos, 75390
- UT Southwestern Medical Center
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Houston, Texas, Estados Unidos, 77030
- Texas Children's Hospital
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Utrecht, Países Bajos, 3584 CX
- Universitair Medisch Centrum Utrecht
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London, Reino Unido, SE5 9RS
- King's College Hospital NHS
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Canton of Bern
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Lausanne, Canton of Bern, Suiza
- CHUV University Hospital of Lausanne
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Ankara, Turquía (Türkiye)
- Hacettepe University
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Istanbul, Turquía (Türkiye), 34093
- İstanbul Üniversitesi Tıp Fakültesi [Istanbul University Faculty of Medicine] Çocuk Sağlığı Enstitüsü [Institute of Child Health]
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Adana
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Izmir, Adana, Turquía (Türkiye)
- Ege University Faculty of Medicine
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
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:
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Pregnant or breastfeeding;
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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;
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History of malignancy;
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History of active and/or uncontrolled cardiac or pulmonary disease or clinically relevant QT prolongation within 6 months before providing informed consent/assent;
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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);
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Renal dysfunction as defined by an estimated glomerular filtration rate <60 milliliters per minute (mL/min)/1.73 m^2;
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Nonfasting triglycerides >440 milligrams per deciliter (mg/dL) (5 millimoles per liter [mmol/L]);
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Active uncontrolled infection requiring systemic antimicrobial therapy;
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Participants with known active hepatitis B or hepatitis C virus infection;
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Participants with known human immunodeficiency virus (HIV) infection;
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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;
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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;
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Prior exposure to gene therapy, or bone marrow or stem cell transplantation;
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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;
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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;
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Receiving anabolic steroids, including testosterone preparations, that have not been stopped for at least 28 days before randomization;
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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);
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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).
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Receiving a pyruvate kinase activator that has not been stopped for ≥52 weeks before providing informed consent/assent.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Cuadruplicar
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: 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). |
Tablets or granules
Otros nombres:
Tablets or granules |
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Comparador de placebos: 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). |
Tablets or granules
Otros nombres:
Tablets or granules |
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Percentage of Participants Achieving Transfusion Reduction Response (TRR)
Periodo de tiempo: Week 9 to Week 32
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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
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Estimación de parámetros del modelo de farmacocinética (PK) poblacional: Concentración plasmática máxima (Cmax) de Mitapivat
Periodo de tiempo: Semanas 2, 8, 12 y 16
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Semanas 2, 8, 12 y 16
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Estimación de parámetros del modelo farmacocinético poblacional: área bajo la curva de concentración-tiempo (AUC) derivada de las concentraciones plasmáticas de Mitapivat
Periodo de tiempo: Semanas 2, 8, 12 y 16
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Semanas 2, 8, 12 y 16
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Concentración en Estado Estacionario (Css) de Mitapivat
Periodo de tiempo: Semana 16: 6 y 8 horas posdosis
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Semana 16: 6 y 8 horas posdosis
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Concentración valle (Cvalle) de Mitapivat
Periodo de tiempo: Semana 8: ≤30 minutos antes de la dosis; Semana 12: ≤30 minutos antes de la dosis
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Semana 8: ≤30 minutos antes de la dosis; Semana 12: ≤30 minutos antes de la dosis
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Cambio desde el inicio en la concentración de estradiol
Periodo de tiempo: Línea de base hasta la semana 298
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Línea de base hasta la semana 298
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Cambio desde el inicio en la concentración de estrona
Periodo de tiempo: Línea de base hasta la semana 298
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Línea de base hasta la semana 298
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Cambio desde el inicio en la concentración total de testosterona
Periodo de tiempo: Línea de base hasta la semana 298
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Línea de base hasta la semana 298
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Cambio desde el inicio en la concentración de testosterona libre en participantes ≥7 años de edad o etapa de Tanner ≥2 (lo que ocurra primero)
Periodo de tiempo: Línea de base hasta la semana 298
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Línea de base hasta la semana 298
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Cambio desde el inicio en la concentración de hormona luteinizante en participantes ≥6 años de edad
Periodo de tiempo: Línea de base hasta la semana 298
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Línea de base hasta la semana 298
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Número de porcentaje de mujeres participantes con desarrollo de quistes ováricos
Periodo de tiempo: Línea de base hasta la semana 298
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Línea de base hasta la semana 298
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Cambio desde el inicio en el tamaño de los quistes ováricos en mujeres participantes
Periodo de tiempo: Línea de base hasta la semana 298
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Línea de base hasta la semana 298
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Cambio desde el punto de referencia en la puntuación Z de talla para la edad
Periodo de tiempo: Línea de base hasta la semana 298
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Línea de base hasta la semana 298
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Cambio desde el inicio en el puntaje Z de peso para la edad
Periodo de tiempo: Línea de base hasta la semana 298
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Línea de base hasta la semana 298
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Cambio desde el inicio en el índice de masa corporal (IMC) para la edad Z-score
Periodo de tiempo: Línea de base hasta la semana 298
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Línea de base hasta la semana 298
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Cambio desde el inicio en la puntuación Z de la densidad mineral ósea (DMO)
Periodo de tiempo: Línea de base hasta la semana 298
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Línea de base hasta la semana 298
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Cambio desde el inicio en la concentración de hierro sérico
Periodo de tiempo: Línea de base hasta la semana 292
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Línea de base hasta la semana 292
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Cambio desde el inicio en la concentración de ferritina sérica
Periodo de tiempo: Línea de base hasta la semana 292
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Línea de base hasta la semana 292
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Cambio desde la línea de base en la capacidad total de fijación de hierro
Periodo de tiempo: Línea de base hasta la semana 292
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Línea de base hasta la semana 292
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Cambio con respecto al valor inicial en transferrina/saturación de transferrina
Periodo de tiempo: Línea de base hasta la semana 292
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Línea de base hasta la semana 292
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Percentage of Participants With Transfusion-free Response
Periodo de tiempo: Week 9 to Week 32
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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
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Change in the Number of Transfusion Episodes
Periodo de tiempo: Week 9 to Week 32
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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
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Percentage Change in Weight-normalized and Study Treatment Duration-normalized Total Transfusion Volume
Periodo de tiempo: Week 9 to Week 32
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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
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Percentage of Participants With Normal Hemoglobin (Hb) Response
Periodo de tiempo: Week 9 to Week 32
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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
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Change From Baseline in Sexual Maturity Rating with Tanner Stage
Periodo de tiempo: Baseline up to Week 298
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Tanner Stage 1 corresponds to the prepubertal form, with progression to Tanner Stage 5, the final adult form. |
Baseline up to Week 298
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Change from Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale
Periodo de tiempo: Baseline up to Week 292
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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
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Change from Baseline in PedsQL Generic Core Scale (GCS)
Periodo de tiempo: Baseline up to Week 292
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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
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Colaboradores e Investigadores
Patrocinador
Investigadores
- Silla de estudio: Medical Affairs, Agios Pharmaceuticals, Inc.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Actual)
Finalización primaria (Actual)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
Otros números de identificación del estudio
- AG348-C-022
- 2021-003265-36 (Número EudraCT)
- 2024-515024-37-00 (Ctis)
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Información sobre medicamentos y dispositivos, documentos del estudio
Estudia un producto farmacéutico regulado por la FDA de EE. UU.
Estudia un producto de dispositivo regulado por la FDA de EE. UU.
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