Рандомизированное адаптивное открытое исследование новых схем лечения легочного туберкулеза с варьирующимися дозами (RAD-TB)
Рандомизированное, адаптивное, открытое исследование фазы 2 новых схем лечения легочного туберкулеза
A5409/RAD-TB is an adaptive Phase 2 randomized, controlled, open-label, dose-ranging, platform protocol to evaluate the safety and efficacy of multidrug regimens for the treatment of adults with drug-susceptible pulmonary tuberculosis (TB).
A5409 hypothesizes that novel regimens for the treatment of pulmonary tuberculosis will result in superior early efficacy, as determined by longitudinal mycobacteria growth indicator tube (MGIT) liquid culture time to positivity (TTP) measurements over the first 6 weeks of treatment, and will have acceptable safety and tolerability over 8 weeks of treatment relative to standard of care [(SOC) isoniazid/rifampicin/pyrazinamide/ethambutol (HRZE)].
The study will run for 52 weeks, inclusive of 26 weeks of TB treatment comprised of 8 weeks of study treatment (experimental or SOC, based on treatment arm assignment) followed by 18 weeks of SOC continuation phase treatment with 346 participants in Wave 1: 49-50 participants in each experimental treatment arm and 98-100 participants in the SOC treatment arm.
Обзор исследования
Статус
Условия
Тип исследования
Регистрация (Оцененный)
Фаза
- Фаза 2
Контакты и местонахождение
Места учебы
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Gaborone, Ботсвана, 0000
- 12701, Gaborone CRS
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Porto Alegre, Бразилия, 91350
- 12201, Instituto de Pesquisas em AIDS do Rio Grande do Sul - IPARGS CRS
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Rio de Janeiro, Бразилия, 21040
- 12101, Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
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Hanoi, Вьетнам, 100000
- 32483 National Lung Hospital CRS
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Port-au-Prince, Гаити, 6110
- 30022, Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
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Port-au-Prince, Гаити, 6110
- 31730, GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS
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Harare, Зимбабве
- 30313, Milton Park CRS
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Pune, Индия, 411001
- 31441, Byramjee Jeejeebhoy Government Medical College (BJGMC) CRS
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Eldoret, Кения, 30100
- 12601, Moi University Clinical Research Center (MUCRC) CRS
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Kericho, Кения, 20200
- 12501, Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
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Blantyre, Малави
- 30301, Blantyre CRS
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Lilongwe, Малави, A-104
- 12001, Malawi CRS
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Mexico City, Мексика, 14080
- 32078, Nutrición-Mexico CRS
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Lima, Перу, 15063
- 11301, Barranco CRS
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Lima, Перу
- 11302, San Miguel CRS San Miguel
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Lima Province
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Lima, Lima Province, Перу, 15234
- 31985, Socios En Salud Sucursal Perú CRS
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Bangkok, Таиланд, 10700
- 5115, Siriraj Hospital, Mahidol University NICHD CRS
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Chiang Mai, Таиланд, 50200
- 31784, Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
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Pathum Wan, Таиланд, 10330
- 31802, Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
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Changwat Chiang Rai
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Chiang Rai, Changwat Chiang Rai, Таиланд, 57000
- 5116 Chiangrai Prachanukroh Hospital NICHD CRS
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Kampala, Уганда
- 12401, Joint Clinical Research Centre (JCRC)/Kampala CRS
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Kampala, Уганда
- 30293 MU-JHU Research Collaboration (MUJHU CARE LTD) CRS
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Cavite, Филиппины, 4118
- 31981, TB HIV Innovations and Clinical Research Foundation Corp.
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Cape Town, Южная Африка, 6850
- 31793, South African Tuberculosis Vaccine Initiative (SATVI) CRS
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Cape Town, Южная Африка, 7700
- 31792, University of Cape Town Lung Institute (UCTLI) CRS
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Durban, Южная Африка, 4001
- 31422, CAPRISA eThekwini CRS
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Durban, Южная Африка, 4052
- 11201, Durban International CRS
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Johannesburg, Южная Африка, 1862
- 12301, Soweto ACTG CRS
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Johannesburg, Южная Африка, 2193
- 11101, Wits Helen Joseph (WITS HJH) CRS
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Rustenburg, Южная Африка
- 31684, Rustenburg CRS
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Критерии участия
Критерии приемлемости
Возраст, подходящий для обучения
Принимает здоровых добровольцев
Полы, имеющие право на обучение
Описание
Inclusion Criteria:
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Pulmonary TB (among individuals either without history of prior TB treatment or with history of TB treatment completed more than 2 years prior to study entry), identified within 7 days prior to study entry by at least one sputum specimen positive for Mtb by Xpert. Semiquantitative Mtb results of "medium" or "high" from Xpert MTB/RIF Ultra are required.
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Pulmonary TB with documented INH susceptibility (by Line Probe Assay (LPA) or Xpert MTB/XDR or other validated molecular test) and with documented RIF susceptibility (by LPA or Xpert MTB/RIF or Xpert MTB/RIF Ultra or other validated molecular test) within 7 days prior to study entry.
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Documentation of HIV-1 infection status, as below:
Presence or absence of HIV-1 infection, as documented by:
- Any licensed rapid HIV test or HIV-1 enzyme or chemiluminescence immunoassay (E/CIA) test kit, any time prior to study entry. AND for a positive result confirmation by one of the following:
- A second antibody test from different manufacturers or based on different principles and epitopes (combination antigen-antibody-based rapid tests may be used), or
- HIV-1 antigen, or
- Plasma HIV-1 RNA viral load, or
- A licensed Western blot
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For individuals with HIV: CD4+ cell count ≥100 cells/mm3 based on testing performed within 30 days prior to study entry.
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For individuals with HIV: Currently being treated with dolutegravir-based antiretroviral therapy (ART), or plan to initiate dolutegravir-based ART at or before study week 8.
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Individuals age ≥18 years.
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The following laboratory values obtained within 7 days prior to study entry at any network-approved non-U.S. laboratory that operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates in appropriate external quality assurance programs:
- Serum or plasma alanine aminotransferase (ALT) ≤3 times the upper limit of normal (ULN)
- Serum or plasma total bilirubin ≤2 times ULN
- Serum or plasma creatinine ≤2 times ULN
- Serum or plasma potassium ≥3.5 mEq/L
- Serum or plasma magnesium ≥1.0 mEq/L (≥0.500 mmol/L)
- Absolute neutrophil count (ANC) ≥1500/mm^3
- Hemoglobin ≥9.0 g/dL
- Platelet count ≥100,000/mm^3
- Negative for, hepatitis B surface antigen (HBsAg)
- Negative for hepatitis C virus (HCV) antibody (or if HCV antibody positive, must have a negative HCV PCR)
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For female study candidates who are of reproductive potential, negative pregnancy test (urine HCG or serum β-HCG) within 3 days (72 hours) prior to entry by any network-approved non-U.S. laboratory or clinic that operates in accordance with GCLP and participates in appropriate external quality assurance programs.
Females who are of reproductive potential and who participate in sexual activity that could lead to pregnancy must agree to use at least two of the following forms of birth control while receiving TB study medications and for 12 months after stopping study medications:
- Male or female condoms
- Diaphragm or cervical cap (with spermicide, if available)
- Intrauterine device (IUD) or intrauterine system (IUS)
- Hormone-based birth control (e.g., oral contraceptives, Depo-Provera, NuvaRing, implants)
Female study candidates who are of reproductive potential, but who abstain from sexual activity that could lead to pregnancy require no additional contraception.
Female study candidates who are not of reproductive potential are eligible without requiring the use of contraceptives. Self-reported history is acceptable documentation of menopause (i.e., at least 1 year amenorrheic), hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; these candidates are all considered not of reproductive potential.
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For male study candidates who engage in sexual activity that may lead to pregnancy in their partner must agree to either remain abstinent or use male contraceptives. They are also strongly advised to inform their non-pregnant sexual partners of reproductive potential to use effective contraceptives while the individual is on study and for 90 days after experimental treatment discontinuation.
For male study candidates who have undergone successful vasectomy with documented azoospermia or have documented azoospermia for any other reason, are eligible without requiring the use of contraceptives.
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For male study candidates with pregnant partners, willingness to use condoms during vaginal intercourse while on study and for 90 days after experimental treatment discontinuation.
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For male study candidates, willingness to refrain from sperm donation while on study and for 90 days after experimental treatment discontinuation.
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Documentation of Karnofsky performance score ≥60 obtained within 14 days prior to study entry.
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Chest x-ray obtained within 14 days prior to study entry.
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A verifiable address or residence readily accessible for visiting, and willingness to inform the study team of any change of address during study treatment and follow-up period.
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Ability and willingness of individual to provide informed consent.
Exclusion Criteria:
- More than cumulative 7 days of treatment directed against active TB for the current TB episode in the 60 days preceding study entry.
- Current extrapulmonary TB, in the opinion of the investigator.
- QTcF interval >450 ms within 7 days prior to study entry.
- History of or ongoing heart failure.
- Personal or family history of congenital QT prolongation.
- History of known, untreated, ongoing hypothyroidism.
- History of or ongoing bradyarrhythmia.
- History of torsades de pointes.
- Current Grade 2 or higher peripheral neuropathy.
- Other medical conditions (e.g., diabetes, liver or kidney disease, blood disorders, chronic diarrhea), in the opinion of the site investigator, in which the current clinical condition of the participant is likely to prejudice the response to, or assessment of, treatment.
- Pregnant or breastfeeding or planning to become pregnant within the next 12 months.
- Weight <35 kg.
- Unable to take oral medications.
- Taking any of prohibited medications.
- Known allergy/sensitivity or any hypersensitivity to components of investigational agents or their formulation.
- Active drug or alcohol use or dependence; or mental illness (e.g., major depression) that, in the opinion of the site investigator, would interfere with adherence to study requirements.
- Taking an investigational drug or vaccine within 30 or more days prior to study entry.
Учебный план
Как устроено исследование?
Детали дизайна
- Основная цель: Уход
- Распределение: Рандомизированный
- Интервенционная модель: Параллельное назначение
- Маскировка: Нет (открытая этикетка)
Оружие и интервенции
Группа участников / Армия |
Вмешательство/лечение |
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Активный компаратор: Arm 1: Standard of Care (SOC)
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INH 300 mg will be administered as one tablet orally once daily.
Другие имена:
RIF 600 mg will be administered as two 300 mg capsules orally once daily on an empty stomach, 1 hour before or 2 hours after eating a meal.
Другие имена:
PZA will be administered as 500 mg tablets, based on weight, orally once daily.
Другие имена:
EMB will be administered as 400 mg tablets, based on weight, orally once daily.
Другие имена:
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Экспериментальный: Arm 2: Bedaquiline (BDQ), Pretomanid (Pa), and Linezolid (LZD)
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INH 300 mg will be administered as one tablet orally once daily.
Другие имена:
RIF 600 mg will be administered as two 300 mg capsules orally once daily on an empty stomach, 1 hour before or 2 hours after eating a meal.
Другие имена:
BDQ 400 mg will be administered as four 100 mg tablets orally once daily with a meal for the first 2 weeks followed by 200 mg (two 100 mg tablets) orally once daily with a meal for 6 weeks.
Другие имена:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Другие имена:
LZD 600 mg will be administered as one 600 mg tablet orally once daily.
Другие имена:
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Экспериментальный: Arm 3A: BDQ, Pa and TBI-223 (1200 mg)
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INH 300 mg will be administered as one tablet orally once daily.
Другие имена:
RIF 600 mg will be administered as two 300 mg capsules orally once daily on an empty stomach, 1 hour before or 2 hours after eating a meal.
Другие имена:
BDQ 400 mg will be administered as four 100 mg tablets orally once daily with a meal for the first 2 weeks followed by 200 mg (two 100 mg tablets) orally once daily with a meal for 6 weeks.
Другие имена:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Другие имена:
TBI-223 2400 mg once daily will be administered as four 600 mg tablets orally once daily with a meal. TBI-223 1200 mg once daily will be administered as two 600 mg tablets orally with a meal. |
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Экспериментальный: Arm 3B: BDQ, Pa and TBI-223 (2400 mg)
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INH 300 mg will be administered as one tablet orally once daily.
Другие имена:
RIF 600 mg will be administered as two 300 mg capsules orally once daily on an empty stomach, 1 hour before or 2 hours after eating a meal.
Другие имена:
BDQ 400 mg will be administered as four 100 mg tablets orally once daily with a meal for the first 2 weeks followed by 200 mg (two 100 mg tablets) orally once daily with a meal for 6 weeks.
Другие имена:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Другие имена:
TBI-223 2400 mg once daily will be administered as four 600 mg tablets orally once daily with a meal. TBI-223 1200 mg once daily will be administered as two 600 mg tablets orally with a meal. |
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Экспериментальный: Arm 4A: BDQ, Pa and Sutezolid (SZD) (800 mg)
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INH 300 mg will be administered as one tablet orally once daily.
Другие имена:
RIF 600 mg will be administered as two 300 mg capsules orally once daily on an empty stomach, 1 hour before or 2 hours after eating a meal.
Другие имена:
BDQ 400 mg will be administered as four 100 mg tablets orally once daily with a meal for the first 2 weeks followed by 200 mg (two 100 mg tablets) orally once daily with a meal for 6 weeks.
Другие имена:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Другие имена:
SZD 1600 mg once daily will be administered as four 400 mg tablets orally once daily with a meal.
Другие имена:
SZD 800 mg once daily will be administered as two 400 mg tablets orally once daily with a meal.
Другие имена:
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Экспериментальный: Arm 4B: BDQ, Pa and SZD (1600 mg)
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INH 300 mg will be administered as one tablet orally once daily.
Другие имена:
RIF 600 mg will be administered as two 300 mg capsules orally once daily on an empty stomach, 1 hour before or 2 hours after eating a meal.
Другие имена:
BDQ 400 mg will be administered as four 100 mg tablets orally once daily with a meal for the first 2 weeks followed by 200 mg (two 100 mg tablets) orally once daily with a meal for 6 weeks.
Другие имена:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Другие имена:
SZD 1600 mg once daily will be administered as four 400 mg tablets orally once daily with a meal.
Другие имена:
SZD 800 mg once daily will be administered as two 400 mg tablets orally once daily with a meal.
Другие имена:
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Что измеряет исследование?
Первичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
|---|---|---|
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Difference in mean log10 (Time to positivity (TTP)) slope from longitudinal mycobacteria growth indicator tube (MGIT) liquid culture measurements over the first 6 weeks of treatment
Временное ограничение: Weeks 0, 1, 2, 3, 4 and 6
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for each experimental treatment arm compared to the SOC treatment arm. |
Weeks 0, 1, 2, 3, 4 and 6
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Difference in the cumulative proportion of participants having at least one new Grade 3 or higher adverse event (AE) by week 8 of treatment
Временное ограничение: 8 weeks
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for each experimental treatment arm compared to the SOC treatment arm. |
8 weeks
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Вторичные показатели результатов
Мера результата |
Временное ограничение |
|---|---|
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Совокупная доля участников со стабильной конверсией культуры мокроты к 8-й неделе, измеренная по отрицательному статусу культуры с помощью жидкой культуры MGIT при двух последовательных измерениях.
Временное ограничение: 8 недель
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8 недель
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Средний наклон log10 TTP по продольным измерениям жидкой культуры MGIT в течение первых 8 недель лечения.
Временное ограничение: Недели 0, 1, 2, 3, 4, 6 и 8
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Недели 0, 1, 2, 3, 4, 6 и 8
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Совокупная доля участников с новым НЯ 3-й степени или выше к 26-й неделе лечения.
Временное ограничение: 26 недель
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26 недель
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Совокупная доля участников, окончательно прекративших прием противотуберкулезных препаратов, входящих в исследование, по любой причине до 8-й недели лечения.
Временное ограничение: 8 недель
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8 недель
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Совокупная доля участников, полностью или временно прекративших прием хотя бы одного противотуберкулезного препарата на срок ≥3 дней по любой причине до 8-й недели лечения.
Временное ограничение: 8 недель
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8 недель
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Совокупная доля участников, полностью прекративших прием хотя бы одного противотуберкулезного препарата по любой причине до 26-й недели лечения.
Временное ограничение: 26 недель
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26 недель
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Комбинация стабильной конверсии культуры на 6-й неделе лечения и отсутствия новых НЯ 3-й степени или выше на 8-й неделе.
Временное ограничение: 8 недель
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8 недель
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Доля участников, достигших устойчивого излечения через 52 недели после начала лечения.
Временное ограничение: 52 недели
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52 недели
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Соавторы и исследователи
Соавторы
Следователи
- Учебный стул: Radojka Savic, PharmD, PhD, University of California
- Учебный стул: Kelly Dooley, MD, PhD, Vanderbilt University Medical Center
- Учебный стул: Gustavo Velásquez, MD, MPH, University of California
Публикации и полезные ссылки
Общие публикации
- Harrison LJ, Velasquez GE, Kempker RR, Imperial MZ, Nuermberger E, Dorman SE, Ignatius E, Granche J, Phillips PPJ, Furin J, Yang E, Foley C, Chiambah S, Rogers R, Van Grack A, Roa J, Shenje J, Nerette S, Kanyama C, Kyeyune RB, Mendoza-Ticona A, Murtaugh W, Foraida S, Goth M, Vernon A, Dooley KE, Savic RM. ACTG A5409 (RAD-TB): Study protocol for a phase 2 randomized, adaptive, dose-ranging, open-label trial of novel regimens for the treatment of pulmonary tuberculosis. Trials. 2025 Aug 15;26(1):291. doi: 10.1186/s13063-025-08973-w.
- Harrison L, Velasquez GE, Kempker RR, Imperial MZ, Nuermberger E, Dorman SE, Ignatius E, Granche J, Phillips PP, Furin J, Yang E, Foley C, Chiambah S, Rogers R, Van Grack A, Roa J, Shenje J, Nerette S, Kanyama C, Kyeyune RB, Mendoza-Ticona A, Murtaugh W, Foraida S, Goth M, Vernon A, Dooley KE, Savic RM. ACTG A5409 (RAD-TB): Study Protocol for a Phase 2 Randomized, Adaptive, Dose-Ranging, Open-Label Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis. Res Sq [Preprint]. 2025 Mar 26:rs.3.rs-5931694. doi: 10.21203/rs.3.rs-5931694/v1.
Даты записи исследования
Изучение основных дат
Начало исследования (Действительный)
Первичное завершение (Оцененный)
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
- Инфекции дыхательных путей
- Инфекции
- Заболевания дыхательных путей
- Легочные заболевания
- Грамположительные бактериальные инфекции
- Бактериальные инфекции
- Бактериальные инфекции и микозы
- Актиномицетовые инфекции
- Микобактериальные инфекции
- Туберкулез
- Туберкулез, Легочный
- Органические химические вещества
- Пиридины
- Гетероциклические соединения, 1-кольцо
- Гетероциклические соединения
- Гетероциклические соединения, слитое кольцо
- Азолы
- Кислоты, ациклические
- Карбоновые кислоты
- Полициклические соединения
- Амиды
- Амины
- Гетероциклические соединения, 4 или более колец
- Рифамицины
- Лактамы, макроциклические
- Макроциклические соединения
- Пиразины
- Ацетамиды
- Ацетаты
- Оксазолидиноны
- Оксазолы
- Гидразины
- Изоникотиновые кислоты
- Кислоты, гетероциклические
- Этилендиамины
- Диамины
- Полиамины
- Линезолид
- Рифампин
- Этамбутол
- Изониазид
- Пиразинамид
- Бедухилин
- Prefotomanid
- PNU-100480
Другие идентификационные номера исследования
- A5409
- DOH-27-032024-5399 (Другой идентификатор: South African National Clinical Trial Registry (SANCTR))
- 38917 (Идентификатор реестра: DAIDS-ES Registry Number)
Планирование данных отдельных участников (IPD)
Планируете делиться данными об отдельных участниках (IPD)?
Описание плана IPD
Individual participant data that underlie results in the publication, after deidentification.
Сроки обмена IPD
Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.
Критерии совместного доступа к IPD
- With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.
- For what types of analyses? To achieve aims in the proposal approved by the AIDS Clinical Trials Group.
- By what mechanism will data be made available? Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/submit-a-proposal/. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.
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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