Исследование по оценке эффективности и безопасности митапивата у участников с трансфузионно-зависимой альфа- или бета-талассемией (α- или β-TDT) (ENERGIZE-T)
Фаза 3, двойное слепое, рандомизированное, плацебо-контролируемое, многоцентровое исследование по оценке эффективности и безопасности митапивата у субъектов с трансфузионно-зависимой альфа- или бета-талассемией (ENERGIZE-T)
The primary objective of this study was to compare the effect of mitapivat versus placebo on transfusion burden in participants with α- or β-transfusion-dependent thalassemia.
Обзор исследования
Статус
Вмешательство/лечение
Подробное описание
The mitapivat group included 171 participants. The placebo group included 87 participants.
Тип исследования
Регистрация (Действительный)
Фаза
- Фаза 3
Контакты и местонахождение
Места учебы
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Kyustendil, Болгария, 2500
- MHAT "Dr. Nikola Vasiliev" AD
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Pleven, Болгария, 5800
- UMHAT "Dr. Georgi Stranski" Pleven
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Plovdiv, Болгария, 4002
- UMHAT "Sveti Georgi" EAD
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Sofia, Болгария, 1756
- SHATHD Sofia
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Stara Zagora, Болгария, 6000
- UMHAT "Prof. Dr. Stoyan Kirkovich"
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Ribeirão Preto, Бразилия, 14051-260
- Hospital Das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
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São Paulo, Бразилия, 04006-002
- GSH Banco de Sangue de São Paulo
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Berlin, Германия, 13353
- Charité - UB - CVK - Medizinische Klinik
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Essen, Германия, 45122
- Universitätsklinikum Essen
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Leipzig, Германия, 04103
- Universitätsklinikum Leipzig
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Achaia, Греция, 26504
- University General Hospital of Patras
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Athens, Греция, 11527
- Children's Hospital Agia Sophia, National and Kapodistrian University of Athens Medical School
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Athens, Греция, 115 26
- Laiko General Hospital
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Ioannina, Греция, 455 00
- University Hospital of Ioannina
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Thessaloniki, Греция, 546 42
- Ippokrateio General Hospital
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Hovedstaden, Дания, 2100
- Rigshospitalet
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Barcelona, Испания, 08035
- Hospital Universitario Vall d'Hebron
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Madrid, Испания, 28046
- Hospital Universitario La Paz
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Murcia, Испания, 30120
- Hospital Universitario Virgen Arrixaca
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Seville, Испания, 41013
- Hospital Universitario Virgen del Rocío
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Brindisi, Италия, 72100
- Ospedale "A. Perrino" - Brindisi
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Cagliari, Италия, 09121
- Ospedale Pediatrico Microcitemico
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Ferrara, Италия, 44124
- Ospedale Sant'Anna
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Genova, Италия, 16128
- Ente Ospedaliero Ospedali Galliera
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Milan, Италия, 20122
- Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
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Modena, Италия, 41124
- A.O.U Di Modena
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Naples, Италия, 80138
- AOU L. Vanvitelli Universita degli Studi della Campania Luigi Vanvitelli
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Orbassano, Италия, 10043
- A.O.U. San Luigi Gonzaga
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Alberta
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Calgary, Alberta, Канада, T2N 2T9
- Foothills Medical Centre
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Ontario
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Toronto, Ontario, Канада, M5G 2C4
- Toronto General Hospital, University Health Network
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Beirut, Ливан, 9999
- Chronic Care Center
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Alor Star, Малайзия, 05460
- Hospital Sultanah Bahiyah
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Johor Bahru, Малайзия, 80100
- Hospital Sultanah Aminah Johor Bahru
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Kota Kinabalu, Малайзия, 88586
- Hospital Queen Elizabeth, Kota Kinabalu
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Kuala Lumpur, Малайзия, 50300
- Hospital Tunku Azizah
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Kuantan, Малайзия, 25100
- Hospital Tengku Ampuan Afzan
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Kuching, Малайзия, 93586
- Hospital Umum Sarawak
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Pandan Indah, Малайзия, 68000
- Hospital Ampang
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Pulau Pinang, Малайзия, 10990
- Hospital Pulau Pinang
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Amsterdam, Нидерланды, 1105 AZ
- Amsterdam Universitair Medisch Centrum, Locatie AMC
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Utrecht, Нидерланды, 3584 CX
- Universitair Medisch Centrum Utrecht
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Westzeedijk 353, Нидерланды, 3015 AA
- Erasmus MC
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Abu Dhabi, Объединенные Арабские Эмираты
- Burjeel Medical City
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Riyadh, Саудовская Аравия, 14611
- King Abdullah International Medical Research Center
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Riyadh, Саудовская Аравия, 90210
- King Khalid University Hospital
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London, Соединенное Королевство, WC1E 6BT
- University College London
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London, Соединенное Королевство, W12 0HS
- Imperial College Healthcare NHS Trust - Hammersmith Hospital
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Arizona
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Phoenix, Arizona, Соединенные Штаты, 85016-7710
- Phoenix Children's Hospital
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California
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La Jolla, California, Соединенные Штаты, 92093
- San Diego Hospital, UC San Diego Health
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Oakland, California, Соединенные Штаты, 94609-1809
- Children's Hospital Oakland
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Palo Alto, California, Соединенные Штаты, 94304-1601
- Stanford Medicine
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Massachusetts
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Boston, Massachusetts, Соединенные Штаты, 02115
- Boston Children's Hospital
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Michigan
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Detroit, Michigan, Соединенные Штаты, 48201-2196
- Children's Hospital of Michigan
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New York
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New York, New York, Соединенные Штаты, 10065-4870
- Weill Cornell Medical Center
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North Carolina
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Durham, North Carolina, Соединенные Штаты, 27710-3038
- Duke University Medical Center
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Pennsylvania
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Philadelphia, Pennsylvania, Соединенные Штаты, 19104
- Penn Medicine - University of Pennsylvania Health System
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Washington
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Seattle, Washington, Соединенные Штаты, 98101
- Seattle Cancer Care Alliance, University of Washington
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Bangkok, Таиланд, 10400
- Phramongkutklao Hospital
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Bangkok, Таиланд, 10400
- Ramathibodi Hospital
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Bangkok, Таиланд, 10700
- Faculty of Medicine Siriraj Hospital
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Chiang Mai, Таиланд, 50200
- Maharaj Nakorn Chiang Mai Hospital
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Khon Kaen, Таиланд, 40000
- Srinagarind Hospital, Khon Kaen University
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Mueang Phitsanulok, Таиланд, 65000
- Naresuan University Hospital
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Pathum Wan, Таиланд
- King Chulalongkorn Memorial Hospital
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Taipei, Тайвань, 100
- National Taiwan University Hospital
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Adana, Турция (Туркие), 1130
- Acibadem Adana Hospital
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Antalya, Турция (Туркие), 07059
- Akdeniz University Faculty of Medicine
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Balcalı, Турция (Туркие), 01330
- Çukurova University
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Bornova, Турция (Туркие), 35040
- Ege University Faculty of Medicine
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Fatih, Турция (Туркие), 34093
- Istanbul University Faculty of Medicine
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Mersin, Турция (Туркие)
- Hacettepe University
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Créteil, Франция, 94010
- CHU Hôpital Henri Mondor
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Lyon, Франция, 69003
- Hôpital Edouard Herriot, CHU de Lyon
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Marseille, Франция, 13385
- CHU Hôpital de la Timone
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Paris, Франция, 75015
- Hôpital Necker Enfants Malades
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Критерии участия
Критерии приемлемости
Возраст, подходящий для обучения
Принимает здоровых добровольцев
Полы, имеющие право на обучение
Описание
Inclusion Criteria:
- Greater than or equal to (≥)18 years of age at the time of providing informed consent;
- Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene mutations, hemoglobin E (HbE)/β-thalassemia, or α-thalassemia/hemoglobin H (HbH) disease) based on deoxyribonucleic acid (DNA) analysis;
- Considered transfusion-dependent, defined as 6 to 20 red blood cells (RBC) units transfused and ≤6-week transfusion-free period during the 24-week period before randomization;
- If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization;
- Women of childbearing potential (WOCBP) must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle or agree to use two forms of contraception, one of which must be considered highly effective, from the time of providing informed consent, throughout the study, and for 28 days after the last dose of study drug. The second form of contraception can be an acceptable barrier method;
- Written informed consent before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.
Exclusion Criteria:
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Pregnant, breastfeeding, or parturient;
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Documented history of homozygous or heterozygous sickle hemoglobin (Hb S) or hemoglobin C (Hb C);
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Prior exposure to gene therapy or prior bone marrow or stem cell transplantation;
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Currently receiving treatment with luspatercept; the last dose must have been administered ≥36 weeks before randomization;
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Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥36 weeks before randomization;
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History of malignancy (active or treated) ≤5 years before providing informed consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ;
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History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent;
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Hepatobiliary disorders;
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Estimated glomerular filtration rate <45 milliliters per minute (mL/min)/1.73 meter (m)^2 by Chronic Kidney Disease Epidemiology Collaboration creatinine equation;
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Nonfasting triglycerides >440 milligrams per deciliter (mg/dL) (5 millimoles per liter [mmol/L]);
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Active infection requiring systemic antimicrobial therapy at the time of providing informed consent;
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Positive test for hepatitis C virus antibody (HCVAb) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg);
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Positive test for human immunodeficiency virus (HIV)-1 antibody (Ab) or HIV-2 Ab;
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History of major surgery (including splenectomy) ≤6 months before providing informed consent and/or a major surgical procedure planned during the study;
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Current enrollment or past participation (≤12 weeks before administration of the first dose of study drug or a timeframe equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational treatment or device;
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Receiving strong CYP3A4/5 inhibitors that have not been stopped for ≥5 days or a timeframe equivalent to 5 half-lives (whichever is longer); or strong CYP3A4 inducers that have not been stopped for ≥4 weeks or a timeframe equivalent to 5 half-lives (whichever is longer), before randomization;
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Receiving anabolic steroids that have not been stopped for at least 4 weeks before randomization. Testosterone replacement therapy to treat hypogonadism is allowed. The testosterone dose and preparation must be stable for ≥12 weeks before randomization;
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Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate, Opadry® II Blue [hypromellose, titanium dioxide, lactose monohydrate, triacetin, and Federal Food, Drug, and Cosmetic (FD&C) Blue #2]);
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Any medical, hematological, 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 excluded 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).
Учебный план
Как устроено исследование?
Детали дизайна
- Основная цель: Уход
- Распределение: Рандомизированный
- Интервенционная модель: Параллельное назначение
- Маскировка: Четырехместный
Оружие и интервенции
Группа участников / Армия |
Вмешательство/лечение |
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Экспериментальный: Mitapivat
Participants randomized to receive mitapivat 100 milligrams (mg), orally, twice daily (BID) for 48 weeks in the double-blind (DB) period and for up to 5 years in the open label extension (OLE) period. |
Tablets
Другие имена:
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Плацебо Компаратор: Placebo
Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the DB period followed by mitapivat 100 mg, orally, BID for up to 5 years in the OLE period. |
Tablets
Другие имена:
Tablets |
Что измеряет исследование?
Первичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
|---|---|---|
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Double-blind Period: Percentage of Participants Who Achieved Transfusion Reduction Response (TRR)
Временное ограничение: Double-blind Period: Baseline through Week 48
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TRR is defined as ≥50% reduction in transfused red blood cells (RBC) units with a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline transfusion burden standardized to 12 weeks. Baseline transfusion burden standardized to 12 weeks= (12/24) × total number of RBC units transfused during 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 12 (Day 85) were considered nonresponders. |
Double-blind Period: Baseline through Week 48
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Вторичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
|---|---|---|
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Двойной слепой период: концентрации митапивата в плазме
Временное ограничение: Двойной слепой период: предварительная доза на 12 неделе; до дозы на 24-й неделе; Предварительная доза, 0,5, 1, 3, 5, 7 часов после дозы на 36 неделе
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Двойной слепой период: предварительная доза на 12 неделе; до дозы на 24-й неделе; Предварительная доза, 0,5, 1, 3, 5, 7 часов после дозы на 36 неделе
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Двойной слепой период: максимальная наблюдаемая концентрация в плазме (CMAX) митапиват
Временное ограничение: Двойной слепой период: предварительная доза, 0,5, 1, 3, 5, 7 часов после дозы 36
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Двойной слепой период: предварительная доза, 0,5, 1, 3, 5, 7 часов после дозы 36
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Двойной слепой период: время до достижения максимальной наблюдаемой концентрации в плазме (TMAX) митапивата
Временное ограничение: Двойной слепой период: предварительная доза, 0,5, 1, 3, 5, 7 часов после дозы 36
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Двойной слепой период: предварительная доза, 0,5, 1, 3, 5, 7 часов после дозы 36
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Двойной слепой период: время последней количественной концентрации (TLAST) митапивата
Временное ограничение: Двойной слепой период: предварительная доза, 0,5, 1, 3, 5, 7 часов после дозы 36
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Двойной слепой период: предварительная доза, 0,5, 1, 3, 5, 7 часов после дозы 36
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Двойной слепой период: концентрация в крови в аденозин-трифосфате (АТФ)
Временное ограничение: Двойной слепой период: предварительная доза на 1-й день; до дозы на 12 неделе; до дозы на 24-й неделе; Предварительная доза, 0,5, 1, 3, 5, 7 часов после дозы на 36 неделе
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Двойной слепой период: предварительная доза на 1-й день; до дозы на 12 неделе; до дозы на 24-й неделе; Предварительная доза, 0,5, 1, 3, 5, 7 часов после дозы на 36 неделе
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Двойной слепой период: концентрация в крови 2,3-дифосфоглицерат (2,3-дпг)
Временное ограничение: Двойной слепой период: предварительная доза на 1-й день; до дозы на 12 неделе; до дозы на 24-й неделе; Предварительная доза, 0,5, 1, 3, 5, 7 часов после дозы на 36 неделе
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Двойной слепой период: предварительная доза на 1-й день; до дозы на 12 неделе; до дозы на 24-й неделе; Предварительная доза, 0,5, 1, 3, 5, 7 часов после дозы на 36 неделе
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Double-blind Period: Percentage of Participants Who Achieved TRR2
Временное ограничение: Double-blind period: Baseline through Week 48
|
TRR2, defined as a ≥50% reduction in transfused RBC units in any consecutive 24-week period through Week 48 compared with the 24-week baseline transfusion burden, is reported. Baseline transfusion burden standardized to 24 weeks is the total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 24 (Day 169) were considered nonresponders. |
Double-blind period: Baseline through Week 48
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Double-blind Period: Percentage of Participants Who Achieved TRR3
Временное ограничение: Double-blind period: Baseline up to Week 13 through Week 48
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TRR3, defined as a ≥33% reduction in transfused RBC units from Week 13 through Week 48 compared with the baseline transfusion burden standardized to 36 weeks, is reported. Baseline transfusion burden standardized to 36 weeks= (36/24) × total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 48 were considered nonresponders. |
Double-blind period: Baseline up to Week 13 through Week 48
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Double-blind Period: Percentage of Participants Who Achieved TRR4
Временное ограничение: Double-blind period: Baseline up to Week 13 through Week 48
|
TRR4, defined as a ≥50% reduction in transfused RBC units from Week 13 through Week 48 compared with the baseline transfusion burden standardized to 36 weeks, is reported. Baseline transfusion burden standardized to 36 weeks = (36/24) × total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 48 were considered nonresponders. |
Double-blind period: Baseline up to Week 13 through Week 48
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Double-blind Period: Percent Change From Baseline in Transfused RBC Units
Временное ограничение: Double-blind Period: Baseline, Week 13 through Week 48
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Transfusion burden from Week 13 through Week 48 standardized to 36 weeks is defined as number of transfused RBC units from Day 85 through Week 48 in the Double-blind Period ×36/(Number of days from Day 85 through Week 48 in the Double-blind Period/7). Baseline transfusion burden standardized to 36 weeks= (36/24)× is the total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or within 168 days before the start of study treatment for participants randomized and dosed. |
Double-blind Period: Baseline, Week 13 through Week 48
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Double-blind Period: Percentage of Participants Who Achieved Transfusion-Independence
Временное ограничение: Double-blind Period: Baseline through Week 48
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Transfusion-independence is defined as transfusion-free for ≥8 consecutive weeks through Week 48 in the double-blind period. |
Double-blind Period: Baseline through Week 48
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Double-blind Period: Change From Baseline in Iron Levels
Временное ограничение: Double-blind Period: Baseline through Week 48
|
Iron metabolism was assessed based on Iron levels. |
Double-blind Period: Baseline through Week 48
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Double-blind Period: Change From Baseline in Serum Ferritin Levels
Временное ограничение: Double-blind Period: Baseline through Week 48
|
Iron metabolism was assessed based on serum ferritin levels. |
Double-blind Period: Baseline through Week 48
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Double-blind Period: Change From Baseline in Total Iron Binding Capacity
Временное ограничение: Double-blind Period: Baseline through Week 48
|
Iron metabolism was assessed based on total iron binding capacity. |
Double-blind Period: Baseline through Week 48
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Double-blind Period: Change From Baseline in Transferrin Saturation (TSAT) Levels
Временное ограничение: Double-blind Period: Baseline through Week 48
|
Iron metabolism was assessed based on TSAT levels. Transferrin saturation is reported by dividing value of serum iron by total iron binding capacity. |
Double-blind Period: Baseline through Week 48
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Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3
Временное ограничение: Double-blind Period: From first dose of study drug up to week 48
|
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and includes both serious & non-serious TEAEs. Severity of AEs was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE. |
Double-blind Period: From first dose of study drug up to week 48
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Open-label Extension Period: Number of Participants With TEAEs, Serious TEAEs, Related TEAEs, Related TEAEs and TEAEs With Severity of Greater Than or Equal to 3
Временное ограничение: Open-Label Extension Period: From Week 48 up to end of study (approximately 5 years)
|
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and includes both serious & non-serious TEAEs. Severity of abnormalities was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE. |
Open-Label Extension Period: From Week 48 up to end of study (approximately 5 years)
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Double-blind Period: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of Mitapivat
Временное ограничение: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
|
Area under the concentration-time curve from time zero to Tlast on dosing day, calculated using the linear-log trapezoidal rule. |
Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
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Double-blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat
Временное ограничение: Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
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Clast is the last quantifiable concentration after a single dose or within the dosing interval (tau) for multiple doses. |
Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
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Соавторы и исследователи
Спонсор
Следователи
- Учебный стул: Medical Affairs, Agios Pharmaceuticals, Inc.
Публикации и полезные ссылки
Даты записи исследования
Изучение основных дат
Начало исследования (Действительный)
Первичное завершение (Действительный)
Завершение исследования (Оцененный)
Даты регистрации исследования
Первый отправленный
Впервые представлено, что соответствует критериям контроля качества
Первый опубликованный (Действительный)
Обновления учебных записей
Последнее опубликованное обновление (Действительный)
Последнее отправленное обновление, отвечающее критериям контроля качества
Последняя проверка
Дополнительная информация
Термины, связанные с этим исследованием
Дополнительные соответствующие термины MeSH
Другие идентификационные номера исследования
- AG348-C-018
- 2021-000212-34 (Номер EudraCT)
- 2024-512747-23-00 (Ктис)
Планирование данных отдельных участников (IPD)
Планируете делиться данными об отдельных участниках (IPD)?
Информация о лекарствах и устройствах, исследовательские документы
Изучает лекарственный продукт, регулируемый FDA США.
Изучает продукт устройства, регулируемый Управлением по санитарному надзору за качеством пищевых продуктов и медикаментов США.
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