Randomizowane, adaptacyjne, otwarte badanie z doborem dawek nowatorskich schematów leczenia gruźlicy płuc (RAD-TB)
Randomizowane, adaptacyjne, otwarte badanie fazy 2 z ustalaniem dawek nowych schematów leczenia gruźlicy płuc
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.
Przegląd badań
Status
Warunki
Typ studiów
Zapisy (Szacowany)
Faza
- Faza 2
Kontakty i lokalizacje
Lokalizacje studiów
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Cape Town, Afryka Południowa, 6850
- 31793, South African Tuberculosis Vaccine Initiative (SATVI) CRS
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Cape Town, Afryka Południowa, 7700
- 31792, University of Cape Town Lung Institute (UCTLI) CRS
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Durban, Afryka Południowa, 4001
- 31422, CAPRISA eThekwini CRS
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Durban, Afryka Południowa, 4052
- 11201, Durban International CRS
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Johannesburg, Afryka Południowa, 1862
- 12301, Soweto ACTG CRS
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Johannesburg, Afryka Południowa, 2193
- 11101, Wits Helen Joseph (WITS HJH) CRS
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Rustenburg, Afryka Południowa
- 31684, Rustenburg CRS
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Gaborone, Botswana, 0000
- 12701, Gaborone CRS
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Porto Alegre, Brazylia, 91350
- 12201, Instituto de Pesquisas em AIDS do Rio Grande do Sul - IPARGS CRS
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Rio de Janeiro, Brazylia, 21040
- 12101, Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
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Cavite, Filipiny, 4118
- 31981, TB HIV Innovations and Clinical Research Foundation Corp.
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Port-au-Prince, Haiti, 6110
- 30022, Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
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Port-au-Prince, Haiti, 6110
- 31730, GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS
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Pune, Indie, 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, Malawi
- 30301, Blantyre CRS
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Lilongwe, Malawi, A-104
- 12001, Malawi CRS
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Mexico City, Meksyk, 14080
- 32078, Nutrición-Mexico CRS
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Lima, Peru, 15063
- 11301, Barranco CRS
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Lima, Peru
- 11302, San Miguel CRS San Miguel
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Lima Province
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Lima, Lima Province, Peru, 15234
- 31985, Socios En Salud Sucursal Perú CRS
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Bangkok, Tajlandia, 10700
- 5115, Siriraj Hospital, Mahidol University NICHD CRS
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Chiang Mai, Tajlandia, 50200
- 31784, Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
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Pathum Wan, Tajlandia, 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, Tajlandia, 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, Wietnam, 100000
- 32483 National Lung Hospital CRS
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Harare, Zimbabwe
- 30313, Milton Park CRS
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Kryteria uczestnictwa
Kryteria kwalifikacji
Wiek uprawniający do nauki
Akceptuje zdrowych ochotników
Płeć kwalifikująca się do nauki
Opis
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 studiów
Jak projektuje się badanie?
Szczegóły projektu
- Główny cel: Leczenie
- Przydział: Randomizowane
- Model interwencyjny: Przydział równoległy
- Maskowanie: Brak (otwarta etykieta)
Broń i interwencje
Grupa uczestników / Arm |
Interwencja / Leczenie |
|---|---|
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Aktywny komparator: Arm 1: Standard of Care (SOC)
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INH 300 mg will be administered as one tablet orally once daily.
Inne nazwy:
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.
Inne nazwy:
PZA will be administered as 500 mg tablets, based on weight, orally once daily.
Inne nazwy:
EMB will be administered as 400 mg tablets, based on weight, orally once daily.
Inne nazwy:
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Eksperymentalny: 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.
Inne nazwy:
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.
Inne nazwy:
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.
Inne nazwy:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Inne nazwy:
LZD 600 mg will be administered as one 600 mg tablet orally once daily.
Inne nazwy:
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Eksperymentalny: 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.
Inne nazwy:
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.
Inne nazwy:
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.
Inne nazwy:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Inne nazwy:
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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Eksperymentalny: 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.
Inne nazwy:
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.
Inne nazwy:
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.
Inne nazwy:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Inne nazwy:
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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Eksperymentalny: 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.
Inne nazwy:
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.
Inne nazwy:
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.
Inne nazwy:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Inne nazwy:
SZD 1600 mg once daily will be administered as four 400 mg tablets orally once daily with a meal.
Inne nazwy:
SZD 800 mg once daily will be administered as two 400 mg tablets orally once daily with a meal.
Inne nazwy:
|
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Eksperymentalny: Arm 4B: BDQ, Pa and SZD (1600 mg)
|
INH 300 mg will be administered as one tablet orally once daily.
Inne nazwy:
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.
Inne nazwy:
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.
Inne nazwy:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Inne nazwy:
SZD 1600 mg once daily will be administered as four 400 mg tablets orally once daily with a meal.
Inne nazwy:
SZD 800 mg once daily will be administered as two 400 mg tablets orally once daily with a meal.
Inne nazwy:
|
Co mierzy badanie?
Podstawowe miary wyniku
Miara wyniku |
Opis środka |
Ramy czasowe |
|---|---|---|
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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
Ramy czasowe: 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
Ramy czasowe: 8 weeks
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for each experimental treatment arm compared to the SOC treatment arm. |
8 weeks
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Miary wyników drugorzędnych
Miara wyniku |
Ramy czasowe |
|---|---|
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Skumulowany odsetek uczestników ze stabilną konwersją posiewu plwociny do 8. tygodnia, mierzony na podstawie statusu ujemnego posiewu za pomocą posiewu płynnego MGIT w dwóch kolejnych pomiarach.
Ramy czasowe: 8 tygodni
|
8 tygodni
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Średnie nachylenie log10 TTP z podłużnych pomiarów płynnej hodowli MGIT w ciągu pierwszych 8 tygodni leczenia.
Ramy czasowe: Tygodnie 0, 1, 2, 3, 4, 6 i 8
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Tygodnie 0, 1, 2, 3, 4, 6 i 8
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Skumulowany odsetek uczestników, u których w 26. tygodniu leczenia wystąpiło nowe zdarzenie niepożądane stopnia 3. lub wyższego.
Ramy czasowe: 26 tygodni
|
26 tygodni
|
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Skumulowany odsetek uczestników, którzy trwale przerwali przyjmowanie dostarczonych w badaniu leków przeciwgruźliczych z dowolnego powodu przed 8. tygodniem leczenia.
Ramy czasowe: 8 tygodni
|
8 tygodni
|
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Skumulowany odsetek uczestników, którzy trwale lub tymczasowo przerwali przyjmowanie na ≥3 dni co najmniej jednego leku przeciwgruźliczego z dowolnej przyczyny przed 8 tygodniem leczenia.
Ramy czasowe: 8 tygodni
|
8 tygodni
|
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Skumulowany odsetek uczestników, którzy trwale przerwali przyjmowanie co najmniej jednego leku przeciwgruźliczego z dowolnego powodu przed 26. tygodniem leczenia.
Ramy czasowe: 26 tygodni
|
26 tygodni
|
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Połączenie stabilnej konwersji hodowli w 6. tygodniu leczenia i braku nowych działań niepożądanych stopnia 3. lub wyższego do 8. tygodnia.
Ramy czasowe: 8 tygodni
|
8 tygodni
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Odsetek uczestników, którzy osiągnęli trwałe wyleczenie w ciągu 52 tygodni od rozpoczęcia leczenia.
Ramy czasowe: 52 tygodnie
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52 tygodnie
|
Współpracownicy i badacze
Współpracownicy
Śledczy
- Krzesło do nauki: Radojka Savic, PharmD, PhD, University of California
- Krzesło do nauki: Kelly Dooley, MD, PhD, Vanderbilt University Medical Center
- Krzesło do nauki: Gustavo Velásquez, MD, MPH, University of California
Publikacje i pomocne linki
Publikacje ogólne
- 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.
Daty zapisu na studia
Główne daty studiów
Rozpoczęcie studiów (Rzeczywisty)
Zakończenie podstawowe (Szacowany)
Ukończenie studiów (Szacowany)
Daty rejestracji na studia
Pierwszy przesłany
Pierwszy przesłany, który spełnia kryteria kontroli jakości
Pierwszy wysłany (Rzeczywisty)
Aktualizacje rekordów badań
Ostatnia wysłana aktualizacja (Rzeczywisty)
Ostatnia przesłana aktualizacja, która spełniała kryteria kontroli jakości
Ostatnia weryfikacja
Więcej informacji
Terminy związane z tym badaniem
Dodatkowe istotne warunki MeSH
- Infekcje dróg oddechowych
- Infekcje
- Choroby Układu Oddechowego
- Choroby płuc
- Zakażenia bakteriami Gram-dodatnimi
- Infekcje bakteryjne
- Infekcje bakteryjne i grzybice
- Infekcje Actinomycetales
- Zakażenia Mykobakterii
- Gruźlica
- Gruźlica, Płuc
- Organiczne chemikalia
- Pirydyny
- Związki heterocykliczne, 1-ring
- Związki heterocykliczne
- Związki heterocykliczne, sterowanie stopieniem
- Azole
- Kwasy, acykliczne
- Kwasy karboksylowe
- Związki policykliczne
- Amides
- Aminy
- Związki heterocykliczne, 4 lub więcej pierścieni
- Rifamycins
- Lactams, makrocykliczny
- Związki makrocykliczne
- Pirazines
- Acetamidy
- Octany
- Oksazolidynony
- Oxazole
- Hydrazyny
- Kwasy isononicynowe
- Kwasy, heterocykliczne
- Etylenodiaminy
- Diakines
- Poliaminowe
- Linezolid
- Ryfampicyna
- Etambutol
- Izoniazyd
- Pirazynamid
- BEDAQUILINE
- Pretomanid
- PNU-100480
Inne numery identyfikacyjne badania
- A5409
- DOH-27-032024-5399 (Inny identyfikator: South African National Clinical Trial Registry (SANCTR))
- 38917 (Identyfikator rejestru: DAIDS-ES Registry Number)
Plan dla danych uczestnika indywidualnego (IPD)
Planujesz udostępniać dane poszczególnych uczestników (IPD)?
Opis planu IPD
Individual participant data that underlie results in the publication, after deidentification.
Ramy czasowe udostępniania IPD
Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.
Kryteria dostępu do udostępniania 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.
Informacje o lekach i urządzeniach, dokumenty badawcze
Bada produkt leczniczy regulowany przez amerykańską FDA
Bada produkt urządzenia regulowany przez amerykańską FDA
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