Um estudo para avaliar a eficácia e a segurança do Mitapivat em participantes pediátricos com deficiência de piruvato quinase (PKD) que são regularmente transfundidos, seguidos por um período de extensão de 5 anos (ACTIVATE-KidsT)
Um estudo de fase 3, multicêntrico, randomizado, duplo-cego, controlado por placebo para avaliar a eficácia e a segurança do mitapivat em pacientes pediátricos com deficiência de piruvato quinase que são regularmente transfundidos, seguido por um período de extensão aberto de 5 anos
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.
Visão geral do estudo
Status
Intervenção / Tratamento
Tipo de estudo
Inscrição (Real)
Estágio
- Fase 3
Contactos e Locais
Locais de estudo
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Berlin, Alemanha, 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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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, Espanha, 08035
- Hospital Universitario Vall d'Hebron
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Madrid, Espanha, 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, Holanda, 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, Suíça
- CHUV University Hospital of Lausanne
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Olomouc, Tcheca, 779 00
- Fakultní Nemocnice Olomouc
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Ankara, Turquia (Türkiye)
- Hacettepe University
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Istanbul, Turquia (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, Turquia (Türkiye)
- Ege University Faculty of Medicine
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
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.
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Randomizado
- Modelo Intervencional: Atribuição Paralela
- Mascaramento: Quadruplicar
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
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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
Outros nomes:
Tablets or granules |
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Comparador de Placebo: 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
Outros nomes:
Tablets or granules |
O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
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Percentage of Participants Achieving Transfusion Reduction Response (TRR)
Prazo: 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 resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
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Estimativa do Parâmetro do Modelo Farmacocinético (PK) da População: Concentração Máxima no Plasma (Cmax) de Mitapivat
Prazo: Semanas 2, 8, 12 e 16
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Semanas 2, 8, 12 e 16
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Estimativa do Parâmetro do Modelo PK da População: Área sob a Curva de Concentração-Tempo (AUC) Derivada das Concentrações Plasmáticas de Mitapivat
Prazo: Semanas 2, 8, 12 e 16
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Semanas 2, 8, 12 e 16
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Concentração em estado estacionário (Css) de Mitapivat
Prazo: Semana 16: 6 e 8 horas após a dose
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Semana 16: 6 e 8 horas após a dose
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Concentração de Vale (Cvale) de Mitapivat
Prazo: Semana 8: ≤30 minutos pré-dose; Semana 12: ≤30 minutos pré-dose
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Semana 8: ≤30 minutos pré-dose; Semana 12: ≤30 minutos pré-dose
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Alteração da linha de base na concentração de estradiol
Prazo: Linha de base até a semana 298
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Linha de base até a semana 298
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Mudança da linha de base na concentração de estrona
Prazo: Linha de base até a semana 298
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Linha de base até a semana 298
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Alteração da linha de base na concentração total de testosterona
Prazo: Linha de base até a semana 298
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Linha de base até a semana 298
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Mudança da linha de base na concentração de testosterona livre em participantes ≥7 anos de idade ou estágio de Tanner ≥2 (o que ocorrer primeiro)
Prazo: Linha de base até a semana 298
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Linha de base até a semana 298
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Mudança da linha de base na concentração de hormônio luteinizante em participantes ≥6 anos de idade
Prazo: Linha de base até a semana 298
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Linha de base até a semana 298
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Número percentual de participantes do sexo feminino com desenvolvimento de cistos ovarianos
Prazo: Linha de base até a semana 298
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Linha de base até a semana 298
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Mudança da linha de base no tamanho dos cistos ovarianos em participantes do sexo feminino
Prazo: Linha de base até a semana 298
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Linha de base até a semana 298
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Alteração da linha de base no escore Z de altura para idade
Prazo: Linha de base até a semana 298
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Linha de base até a semana 298
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Alteração da linha de base no escore Z de peso para idade
Prazo: Linha de base até a semana 298
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Linha de base até a semana 298
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Mudança da linha de base no índice de massa corporal (IMC) para a idade Z-score
Prazo: Linha de base até a semana 298
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Linha de base até a semana 298
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Mudança da linha de base no Z-score de Densidade Mineral Óssea (BMD)
Prazo: Linha de base até a semana 298
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Linha de base até a semana 298
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Mudança da linha de base na concentração de ferro sérico
Prazo: Linha de base até a semana 292
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Linha de base até a semana 292
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Alteração da linha de base na concentração de ferritina sérica
Prazo: Linha de base até a semana 292
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Linha de base até a semana 292
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Mudança da linha de base na capacidade total de ligação de ferro
Prazo: Linha de base até a semana 292
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Linha de base até a semana 292
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Alteração da linha de base na saturação de transferrina/transferrina
Prazo: Linha de base até a semana 292
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Linha de base até a semana 292
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Percentage of Participants With Transfusion-free Response
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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)
Prazo: 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
- Cadeira de estudo: Medical Affairs, Agios Pharmaceuticals, Inc.
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo (Real)
Conclusão Primária (Real)
Conclusão do estudo (Estimado)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Real)
Atualizações de registro de estudo
Última Atualização Postada (Real)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Palavras-chave
Termos MeSH relevantes adicionais
Outros números de identificação do estudo
- AG348-C-022
- 2021-003265-36 (Número EudraCT)
- 2024-515024-37-00 (Ctis)
Plano para dados de participantes individuais (IPD)
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