Randomizovaná, adaptivní, dávka-rozsahující, otevřená studie s novými režimy pro léčbu plicní tuberkulózy (RAD-TB)
Randomizovaná, adaptivní, dávka-rozsahující, otevřená studie fáze 2 s novými režimy pro léčbu plicní tuberkulózy
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.
Přehled studie
Postavení
Podmínky
Typ studie
Zápis (Odhadovaný)
Fáze
- Fáze 2
Kontakty a umístění
Studijní místa
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Gaborone, Botswana, 0000
- 12701, Gaborone CRS
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Porto Alegre, Brazílie, 91350
- 12201, Instituto de Pesquisas em AIDS do Rio Grande do Sul - IPARGS CRS
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Rio de Janeiro, Brazílie, 21040
- 12101, Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
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Cavite, Filipíny, 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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Cape Town, Jižní Afrika, 6850
- 31793, South African Tuberculosis Vaccine Initiative (SATVI) CRS
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Cape Town, Jižní Afrika, 7700
- 31792, University of Cape Town Lung Institute (UCTLI) CRS
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Durban, Jižní Afrika, 4001
- 31422, CAPRISA eThekwini CRS
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Durban, Jižní Afrika, 4052
- 11201, Durban International CRS
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Johannesburg, Jižní Afrika, 1862
- 12301, Soweto ACTG CRS
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Johannesburg, Jižní Afrika, 2193
- 11101, Wits Helen Joseph (WITS HJH) CRS
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Rustenburg, Jižní Afrika
- 31684, Rustenburg CRS
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Eldoret, Keňa, 30100
- 12601, Moi University Clinical Research Center (MUCRC) CRS
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Kericho, Keňa, 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, Mexiko, 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, Thajsko, 10700
- 5115, Siriraj Hospital, Mahidol University NICHD CRS
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Chiang Mai, Thajsko, 50200
- 31784, Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
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Pathum Wan, Thajsko, 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, Thajsko, 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, Zimbabwe
- 30313, Milton Park CRS
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Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
Přijímá zdravé dobrovolníky
Pohlaví způsobilá ke studiu
Popis
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.
Studijní plán
Jak je studie koncipována?
Detaily designu
- Primární účel: Léčba
- Přidělení: Randomizované
- Intervenční model: Paralelní přiřazení
- Maskování: Žádné (otevřený štítek)
Zbraně a zásahy
Skupina účastníků / Arm |
Intervence / Léčba |
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Aktivní komparátor: Arm 1: Standard of Care (SOC)
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INH 300 mg will be administered as one tablet orally once daily.
Ostatní jména:
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.
Ostatní jména:
PZA will be administered as 500 mg tablets, based on weight, orally once daily.
Ostatní jména:
EMB will be administered as 400 mg tablets, based on weight, orally once daily.
Ostatní jména:
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Experimentální: 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.
Ostatní jména:
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.
Ostatní jména:
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.
Ostatní jména:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Ostatní jména:
LZD 600 mg will be administered as one 600 mg tablet orally once daily.
Ostatní jména:
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Experimentální: 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.
Ostatní jména:
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.
Ostatní jména:
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.
Ostatní jména:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Ostatní jména:
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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Experimentální: 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.
Ostatní jména:
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.
Ostatní jména:
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.
Ostatní jména:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Ostatní jména:
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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Experimentální: 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.
Ostatní jména:
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.
Ostatní jména:
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.
Ostatní jména:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Ostatní jména:
SZD 1600 mg once daily will be administered as four 400 mg tablets orally once daily with a meal.
Ostatní jména:
SZD 800 mg once daily will be administered as two 400 mg tablets orally once daily with a meal.
Ostatní jména:
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Experimentální: Arm 4B: BDQ, Pa and SZD (1600 mg)
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INH 300 mg will be administered as one tablet orally once daily.
Ostatní jména:
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.
Ostatní jména:
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.
Ostatní jména:
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
Ostatní jména:
SZD 1600 mg once daily will be administered as four 400 mg tablets orally once daily with a meal.
Ostatní jména:
SZD 800 mg once daily will be administered as two 400 mg tablets orally once daily with a meal.
Ostatní jména:
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Co je měření studie?
Primární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
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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
Časové okno: 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
Časové okno: 8 weeks
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for each experimental treatment arm compared to the SOC treatment arm. |
8 weeks
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Sekundární výstupní opatření
Měření výsledku |
Časové okno |
|---|---|
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Kumulativní podíl účastníků se stabilní konverzí kultivace sputa do 8. týdne, měřený podle kultivačního negativního stavu pomocí tekuté kultury MGIT při dvou po sobě jdoucích měřeních.
Časové okno: 8 týdnů
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8 týdnů
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Střední log10 sklon TTP z podélných měření tekuté kultury MGIT během prvních 8 týdnů léčby.
Časové okno: Týdny 0, 1, 2, 3, 4, 6 a 8
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Týdny 0, 1, 2, 3, 4, 6 a 8
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Kumulativní podíl účastníků s novým AE stupně 3 nebo vyšším do 26. týdne léčby.
Časové okno: 26 týdnů
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26 týdnů
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Kumulativní podíl účastníků s trvalým vysazením léků proti TBC poskytovaných ve studii z jakéhokoli důvodu před 8. týdnem léčby.
Časové okno: 8 týdnů
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8 týdnů
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Kumulativní podíl účastníků s trvalým nebo dočasným přerušením užívání alespoň jednoho léku proti TBC z jakéhokoli důvodu po dobu ≥ 3 dnů před týdnem 8 léčby.
Časové okno: 8 týdnů
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8 týdnů
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Kumulativní podíl účastníků s trvalým vysazením alespoň jednoho léku proti TBC z jakéhokoli důvodu před 26. týdnem léčby.
Časové okno: 26 týdnů
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26 týdnů
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Kompozit stabilní konverze kultury v 6. týdnu léčby a žádné nové AE stupně 3 nebo vyšší do 8. týdne.
Časové okno: 8 týdnů
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8 týdnů
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Podíl účastníků s trvalou léčbou do 52 týdnů po zahájení léčby.
Časové okno: 52 týdnů
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52 týdnů
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Spolupracovníci a vyšetřovatelé
Spolupracovníci
Vyšetřovatelé
- Studijní židle: Radojka Savic, PharmD, PhD, University of California
- Studijní židle: Kelly Dooley, MD, PhD, Vanderbilt University Medical Center
- Studijní židle: Gustavo Velásquez, MD, MPH, University of California
Publikace a užitečné odkazy
Obecné publikace
- 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.
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia (Aktuální)
Primární dokončení (Odhadovaný)
Dokončení studie (Odhadovaný)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Aktuální)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Aktuální)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
Naposledy ověřeno
Více informací
Termíny související s touto studií
Další relevantní podmínky MeSH
- Infekce dýchacích cest
- Infekce
- Nemoci dýchacích cest
- Plicní onemocnění
- Gram-pozitivní bakteriální infekce
- Bakteriální infekce
- Bakteriální infekce a mykózy
- Infekce Actinomycetales
- Infekce Mycobacterium
- Tuberkulóza
- Tuberkulóza, plicní
- Organické chemikálie
- Pyridiny
- Heterocyklické sloučeniny, 1 kruh
- Heterocyklické sloučeniny
- Heterocyklické sloučeniny, fúzované kroužek
- Azoly
- Kyseliny, acyklické
- Karboxylové kyseliny
- Polycyklické sloučeniny
- Amidy
- Aminy
- Heterocyklické sloučeniny, 4 nebo více prstenů
- Rifamyciny
- Laktams, makrocyklické
- Makrocyklické sloučeniny
- Pyraziny
- Acetamidy
- Acetáty
- Oxazolidinony
- Oxazoly
- Hydraziny
- Isonikotinové kyseliny
- Kyseliny, heterocyklické
- Ethylendiamins
- Diaminy
- Polyaminy
- Linezolid
- Rifampin
- Ethambutol
- Isoniazid
- Pyrazinamid
- Bedaquilin
- Predomanid
- PNU-100480
Další identifikační čísla studie
- A5409
- DOH-27-032024-5399 (Jiný identifikátor: South African National Clinical Trial Registry (SANCTR))
- 38917 (Identifikátor registru: DAIDS-ES Registry Number)
Plán pro data jednotlivých účastníků (IPD)
Plánujete sdílet data jednotlivých účastníků (IPD)?
Popis plánu IPD
Individual participant data that underlie results in the publication, after deidentification.
Časový rámec sdílení IPD
Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.
Kritéria přístupu pro sdílení 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.
Informace o lécích a zařízeních, studijní dokumenty
Studuje lékový produkt regulovaný americkým FDA
Studuje produkt zařízení regulovaný americkým úřadem FDA
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