NCT06192160招募中2 期
A Phase 2 Randomized, Adaptive, Dose-Ranging, Open-Label Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis
National Institute of Allergy and Infectious Diseases (NIAID)30 个研究点 分布在 14 个国家目标入组 315 人开始时间: 2025年3月11日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 315
- 试验地点
- 30
- 主要终点
- Difference in the cumulative proportion of participants having at least one new Grade 3 or higher adverse event (AE) by week 8 of treatment
研究概览
简要总结
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 45 participants in each experimental treatment arm and at least 90 participants in the SOC arm.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •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.
- •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
- •For individuals with HIV: CD4+ cell count ≥100 cells/mm3 based on testing performed within 30 days prior to study entry.
- •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
- •Individuals age ≥18 years.
- •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)
- •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.
- •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.
- •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.
- •For male study candidates, willingness to refrain from sperm donation while on study and for 90 days after experimental treatment discontinuation.
- •Documentation of Karnofsky performance score ≥60 obtained within 14 days prior to study entry.
- •Chest x-ray obtained within 14 days prior to study entry.
- •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.
- •Ability and willingness of individual to provide informed consent.
排除标准
- •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.
研究组 & 干预措施
Arm 1: Standard of Care (SOC)
Active Comparator
- Weeks 1-8: INH 300 mg, RIF 600 mg, PZA weight-based, EMB weight-based
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Ethambutol (Drug)
Arm 3A: BDQ, Pa and TBI-223 (1200 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, TBI-223 1200 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Rifampicin (Drug)
Arm 4B: BDQ, Pa and SZD (1600 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, SZD 1600 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Bedaquiline (Drug)
Arm 4A: BDQ, Pa and Sutezolid (SZD) (800 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, SZD 800 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Bedaquiline (Drug)
Arm 2: Bedaquiline (BDQ), Pretomanid (Pa), and Linezolid (LZD)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, LZD 600 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Bedaquiline (Drug)
Arm 3B: BDQ, Pa and TBI-223 (2400 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, TBI-223 2400 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Rifampicin (Drug)
Arm 2: Bedaquiline (BDQ), Pretomanid (Pa), and Linezolid (LZD)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, LZD 600 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Pretomanid (Drug)
Arm 3A: BDQ, Pa and TBI-223 (1200 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, TBI-223 1200 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Isoniazid (Drug)
Arm 1: Standard of Care (SOC)
Active Comparator
- Weeks 1-8: INH 300 mg, RIF 600 mg, PZA weight-based, EMB weight-based
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Isoniazid (Drug)
Arm 1: Standard of Care (SOC)
Active Comparator
- Weeks 1-8: INH 300 mg, RIF 600 mg, PZA weight-based, EMB weight-based
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Rifampicin (Drug)
Arm 2: Bedaquiline (BDQ), Pretomanid (Pa), and Linezolid (LZD)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, LZD 600 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Linezolid (Drug)
Arm 3B: BDQ, Pa and TBI-223 (2400 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, TBI-223 2400 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Bedaquiline (Drug)
Arm 3B: BDQ, Pa and TBI-223 (2400 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, TBI-223 2400 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Pretomanid (Drug)
Arm 3B: BDQ, Pa and TBI-223 (2400 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, TBI-223 2400 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Isoniazid (Drug)
Arm 4A: BDQ, Pa and Sutezolid (SZD) (800 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, SZD 800 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Rifampicin (Drug)
Arm 4B: BDQ, Pa and SZD (1600 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, SZD 1600 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Sutezolid (Drug)
Arm 3A: BDQ, Pa and TBI-223 (1200 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, TBI-223 1200 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Bedaquiline (Drug)
Arm 1: Standard of Care (SOC)
Active Comparator
- Weeks 1-8: INH 300 mg, RIF 600 mg, PZA weight-based, EMB weight-based
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Pyrazinamide (Drug)
Arm 2: Bedaquiline (BDQ), Pretomanid (Pa), and Linezolid (LZD)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, LZD 600 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Isoniazid (Drug)
Arm 2: Bedaquiline (BDQ), Pretomanid (Pa), and Linezolid (LZD)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, LZD 600 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Rifampicin (Drug)
Arm 3A: BDQ, Pa and TBI-223 (1200 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, TBI-223 1200 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Pretomanid (Drug)
Arm 3A: BDQ, Pa and TBI-223 (1200 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, TBI-223 1200 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: TBI-223 (Drug)
Arm 3B: BDQ, Pa and TBI-223 (2400 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, TBI-223 2400 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: TBI-223 (Drug)
Arm 4A: BDQ, Pa and Sutezolid (SZD) (800 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, SZD 800 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Isoniazid (Drug)
Arm 4B: BDQ, Pa and SZD (1600 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, SZD 1600 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Rifampicin (Drug)
Arm 4A: BDQ, Pa and Sutezolid (SZD) (800 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, SZD 800 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Sutezolid (Drug)
Arm 4A: BDQ, Pa and Sutezolid (SZD) (800 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, SZD 800 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Pretomanid (Drug)
Arm 4B: BDQ, Pa and SZD (1600 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, SZD 1600 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Isoniazid (Drug)
Arm 4B: BDQ, Pa and SZD (1600 mg)
Experimental
- Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, SZD 1600 mg
- Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)
干预措施: Pretomanid (Drug)
结局指标
主要结局
Difference in the cumulative proportion of participants having at least one new Grade 3 or higher adverse event (AE) by week 8 of treatment
时间窗: 8 weeks
for each experimental treatment arm compared to the SOC treatment arm.
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
时间窗: Weeks 0, 1, 2, 3, 4 and 6
for each experimental treatment arm compared to the SOC treatment arm.
次要结局
- Cumulative proportion of participants with stable sputum culture conversion by week 8 as measured by culture-negative status via MGIT liquid culture at two consecutive measurements.(8 weeks)
- Cumulative proportion of participants with a new Grade 3 or higher AE by week 26 of treatment.(26 weeks)
- Proportion of participants with durable cure by 52 weeks after treatment initiation.(52 Weeks)
- Mean log10 TTP slope from longitudinal MGIT liquid culture measurements over the first 8 weeks of treatment.(Weeks 0, 1, 2, 3, 4, 6 and 8)
- A composite of stable culture conversion at week 6 of treatment and no new Grade 3 or higher AE through week 8.(8 weeks)
- Cumulative proportion of participants with permanent discontinuation or temporary discontinuation for ≥3 days of at least one anti-TB drug due to any reason prior to week 8 of treatment.(8 weeks)
- Cumulative proportion of participants with permanent discontinuation of study-provided anti-TB drugs due to any reason prior to Week 8 of treatment.(8 weeks)
- Cumulative proportion of participants with permanent discontinuation of at least one anti-TB drug due to any reason prior to week 26 of treatment.(26 weeks)
研究者
研究点 (30)
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