Un ensayo abierto, aleatorizado, adaptativo y con rango de dosis de nuevos regímenes para el tratamiento de la tuberculosis pulmonar (RAD-TB)
Un ensayo de fase 2, aleatorizado, adaptativo, de rango de dosis y de etiqueta abierta de nuevos regímenes para el tratamiento de la tuberculosis pulmonar
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.
Descripción general del estudio
Estado
Estado
Condiciones
Condiciones
Intervención / Tratamiento
Intervención / Tratamiento
Tipo de estudio
Tipo de estudio
Inscripción (Estimado)
Inscripción
Fase
Fase
- Fase 2
Contactos y Ubicaciones
Ubicaciones de estudio
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Gaborone, Botsuana, 0000
- 12701, Gaborone CRS
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Porto Alegre, Brasil, 91350
- 12201, Instituto de Pesquisas em AIDS do Rio Grande do Sul - IPARGS CRS
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Rio de Janeiro, Brasil, 21040
- 12101, Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
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Cavite, Filipinas, 4118
- 31981, TB HIV Innovations and Clinical Research Foundation Corp.
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Port-au-Prince, Haití, 6110
- 30022, Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
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Port-au-Prince, Haití, 6110
- 31730, GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS
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Pune, India, 411001
- 31441, Byramjee Jeejeebhoy Government Medical College (BJGMC) CRS
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Eldoret, Kenia, 30100
- 12601, Moi University Clinical Research Center (MUCRC) CRS
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Kericho, Kenia, 20200
- 12501, Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
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Blantyre, Malaui
- 30301, Blantyre CRS
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Lilongwe, Malaui, A-104
- 12001, Malawi CRS
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Mexico City, México, 14080
- 32078, Nutrición-Mexico CRS
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Lima, Perú, 15063
- 11301, Barranco CRS
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Lima, Perú
- 11302, San Miguel CRS San Miguel
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Lima Province
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Lima, Lima Province, Perú, 15234
- 31985, Socios En Salud Sucursal Perú CRS
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Cape Town, Sudáfrica, 6850
- 31793, South African Tuberculosis Vaccine Initiative (SATVI) CRS
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Cape Town, Sudáfrica, 7700
- 31792, University of Cape Town Lung Institute (UCTLI) CRS
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Durban, Sudáfrica, 4001
- 31422, CAPRISA eThekwini CRS
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Durban, Sudáfrica, 4052
- 11201, Durban International CRS
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Johannesburg, Sudáfrica, 1862
- 12301, Soweto ACTG CRS
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Johannesburg, Sudáfrica, 2193
- 11101, Wits Helen Joseph (WITS HJH) CRS
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Rustenburg, Sudáfrica
- 31684, Rustenburg CRS
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Bangkok, Tailandia, 10700
- 5115, Siriraj Hospital, Mahidol University NICHD CRS
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Chiang Mai, Tailandia, 50200
- 31784, Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
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Pathum Wan, Tailandia, 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, Tailandia, 57000
- 5116 Chiangrai Prachanukroh Hospital NICHD CRS
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Kampala, Uganda
- 12401, Joint Clinical Research Centre (JCRC)/Kampala CRS
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Kampala, Uganda
- 30293 MU-JHU Research Collaboration (MUJHU CARE LTD) CRS
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Hanoi, Vietnam, 100000
- 32483 National Lung Hospital CRS
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Harare, Zimbabue
- 30313, Milton Park CRS
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Criterios de participación
Criterio de elegibilidad
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
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.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Ninguno (etiqueta abierta)
Número de brazos
Armas e Intervenciones
Grupo de participantes/brazoGrupo de participantes/brazo |
Intervención / TratamientoIntervención / Tratamiento |
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Comparador activo: Arm 1: Standard of Care (SOC)
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INH 300 mg will be administered as one tablet orally once daily.
Otros nombres:
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.
Otros nombres:
PZA will be administered as 500 mg tablets, based on weight, orally once daily.
Otros nombres:
EMB will be administered as 400 mg tablets, based on weight, orally once daily.
Otros nombres:
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Experimental: 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.
Otros nombres:
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.
Otros nombres:
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.
Otros nombres:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Otros nombres:
LZD 600 mg will be administered as one 600 mg tablet orally once daily.
Otros nombres:
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Experimental: 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.
Otros nombres:
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.
Otros nombres:
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.
Otros nombres:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Otros nombres:
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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Experimental: 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.
Otros nombres:
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.
Otros nombres:
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.
Otros nombres:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Otros nombres:
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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Experimental: 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.
Otros nombres:
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.
Otros nombres:
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.
Otros nombres:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Otros nombres:
SZD 1600 mg once daily will be administered as four 400 mg tablets orally once daily with a meal.
Otros nombres:
SZD 800 mg once daily will be administered as two 400 mg tablets orally once daily with a meal.
Otros nombres:
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Experimental: Arm 4B: BDQ, Pa and SZD (1600 mg)
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INH 300 mg will be administered as one tablet orally once daily.
Otros nombres:
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.
Otros nombres:
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.
Otros nombres:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Otros nombres:
SZD 1600 mg once daily will be administered as four 400 mg tablets orally once daily with a meal.
Otros nombres:
SZD 800 mg once daily will be administered as two 400 mg tablets orally once daily with a meal.
Otros nombres:
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¿Qué mide el estudio?
Medidas de resultado primarias
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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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
Periodo de tiempo: 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
Periodo de tiempo: 8 weeks
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for each experimental treatment arm compared to the SOC treatment arm. |
8 weeks
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Medidas de resultado secundarias
Medidas de resultado secundarias
Medida de resultado |
Periodo de tiempo |
|---|---|
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Proporción acumulada de participantes con conversión estable del cultivo de esputo en la semana 8, medida por el estado de cultivo negativo mediante cultivo líquido MGIT en dos mediciones consecutivas.
Periodo de tiempo: 8 semanas
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8 semanas
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Pendiente media de log10 TTP a partir de mediciones longitudinales del cultivo líquido MGIT durante las primeras 8 semanas de tratamiento.
Periodo de tiempo: Semanas 0, 1, 2, 3, 4, 6 y 8
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Semanas 0, 1, 2, 3, 4, 6 y 8
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Proporción acumulada de participantes con un nuevo EA de Grado 3 o superior en la semana 26 de tratamiento.
Periodo de tiempo: 26 semanas
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26 semanas
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Proporción acumulada de participantes con interrupción permanente de los medicamentos antituberculosos proporcionados en el estudio por cualquier motivo antes de la semana 8 de tratamiento.
Periodo de tiempo: 8 semanas
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8 semanas
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Proporción acumulada de participantes con interrupción permanente o interrupción temporal durante ≥3 días de al menos un medicamento contra la tuberculosis debido a cualquier motivo antes de la semana 8 de tratamiento.
Periodo de tiempo: 8 semanas
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8 semanas
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Proporción acumulada de participantes con interrupción permanente de al menos un fármaco contra la tuberculosis por cualquier motivo antes de la semana 26 de tratamiento.
Periodo de tiempo: 26 semanas
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26 semanas
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Una combinación de conversión de cultivo estable en la semana 6 de tratamiento y ningún EA nuevo de Grado 3 o superior hasta la semana 8.
Periodo de tiempo: 8 semanas
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8 semanas
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Proporción de participantes con curación duradera a las 52 semanas después del inicio del tratamiento.
Periodo de tiempo: 52 Semanas
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52 Semanas
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Colaboradores e Investigadores
Patrocinador
Patrocinador
Colaboradores
Colaboradores
Investigadores
Investigadores
- Silla de estudio: Radojka Savic, PharmD, PhD, University of California
- Silla de estudio: Kelly Dooley, MD, PhD, Vanderbilt University Medical Center
- Silla de estudio: Gustavo Velásquez, MD, MPH, University of California
Publicaciones y enlaces útiles
Publicaciones Generales
- 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.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Actual)
Inicio del estudio
Finalización primaria (Estimado)
Finalización primaria
Finalización del estudio (Estimado)
Finalización del estudio
Fechas de registro del estudio
Enviado por primera vez
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Publicado por primera vez
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización publicada
Última actualización enviada que cumplió con los criterios de control de calidad
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Última verificación
Más información
Términos relacionados con este estudio
Términos MeSH relevantes adicionales
- Infecciones del Tracto Respiratorio
- Infecciones
- Enfermedades de las vías respiratorias
- Enfermedades pulmonares
- Infecciones por bacterias grampositivas
- Infecciones bacterianas
- Infecciones bacterianas y micosis
- Infecciones por Actinomycetales
- Infecciones por micobacterias
- Tuberculosis
- Tuberculosis Pulmonar
- Químicos orgánicos
- Piridina
- Compuestos heterocíclicos, 1 anillo
- Compuestos heterocíclicos
- Compuestos heterocíclicos, anillo fusionado
- Azoles
- Ácidos, acíclico
- Ácidos carboxílicos
- Compuestos policíclicos
- Amidas
- Amina
- Compuestos heterocíclicos, 4 o más anillos
- Rifamycinas
- Lactamas, macrocíclicas
- Compuestos macrocíclicos
- Pirazinas
- Acetamidas
- Acetato
- Oxazolidinonas
- Oxazoles
- Hidrazinas
- Ácidos isonicotínicos
- Ácidos, heterocíclicos
- Etilendiaminas
- Diamina
- Poliamina
- Linezolida
- Rifampicina
- Etambutol
- Isoniazida
- Pirazinamida
- bedaquilina
- pretomaní
- PNU-100480
Otros números de identificación del estudio
Otros números de identificación del estudio
- A5409
- DOH-27-032024-5399 (Otro identificador: South African National Clinical Trial Registry (SANCTR))
- 38917 (Identificador de registro: DAIDS-ES Registry Number)
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Descripción del plan IPD
Individual participant data that underlie results in the publication, after deidentification.
Marco de tiempo para compartir IPD
Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.
Criterios de acceso compartido de 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.
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.
Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .