Optimal Treatment Duration for Radiographically Apparent, Bacteriologically Unconfirmed TB, Identified Through Active Case Finding
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 784
- 试验地点
- 4
- 主要终点
- Proportion of participants with an unfavourable TB outcome
研究概览
简要总结
People living in high TB burden communities who undergo active case finding for TB may have chest X-ray changes suggestive of TB but their sputum test can be negative for the TB bacteria or they are unable to provide a sputum sample. This means they have bacteriologically unconfirmed TB. These individuals often have minimal or no symptoms and face uncertainty in clinical management-either receiving full 24-weeks TB treatment or often being discharged without treatment, risking loss to follow-up.
The RADIO-TB trial aims to address the following main questions in relation to people with bacteriologically unconfirmed TB.
- What is the risk of progression if treatment is not immediately started but there is close and careful follow-up over 78 weeks?
- If treatment is started immediately what is the shortest duration of TB treatment that is as effective as the standard 24-week TB treatment?
- Are there better tests to confirm TB than the current routinely used, sputum-based tests?
- What is the cost effectiveness of different treatment strategies and what might the impact on transmission be within communities?
Participants in the trial will be randomized into six groups: five receiving immediate standard TB treatment of varying durations (8 to 24 weeks), and one receiving deferred treatment with close monitoring. Deferred treatment will be initiated only if clinical deterioration occurs or TB is later confirmed. Participants will be closely followed for 78 weeks with at least 11 clinic visits.
详细描述
Increasingly, countries are adopting community-based chest X-ray (CXR) screening strategies to identify people with TB at an early stage, often before they have symptoms. However, a significant proportion of individuals with radiographic abnormalities suggestive of TB are not bacteriologically confirmed due to limitations in sputum-based diagnostics or inability to produce sputum. These individuals are often diagnosed with "bacteriologically unconfirmed TB," and there is currently no consensus on how best to manage them.
The RADIO-TB trial is a multi-country, multi-arm, phase 3 clinical trial designed to address this critical evidence gap. The trial aims to determine the optimal treatment duration for individuals with radiographic evidence of TB who do not have bacteriological confirmation and are identified through active case finding (ACF) using CXR and computer-aided detection (CAD) software. The study is being conducted in South Africa, Zimbabwe, and Pakistan. Recruitment for the trial will be conducted alongside existing programatic CXR-based TB ACF activity taking place in these countries.
RADIO-TB uses a pragmatic, open-label, randomized design with six parallel arms. Participants are randomized to one of the following 6 arms in a ratio 1:1:1:1:1:2.
Arm A. Immediate start of 24 weeks (approx. 6 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 16 weeks (approx. 4 months) of isoniazid and rifampicin (4HR) - 2HRZE/4HR (control-A).
Arm B. Immediate start of 20 weeks (approx. 5 months) TB treatment - 2HRZE/3HR. Arm C. Immediate start of 16 weeks (approx. 4 months) TB treatment - 2HRZE/2HR. Arm D. Immediate start of 12 weeks (approx. 3 months) TB treatment - 2HRZE/1HR. Arm E. Immediate start of 8 weeks (approx. 2 months) TB treatment - 2HRZE. Arm F. No initial treatment, deferred if progression - if during close follow-up there is bacteriological confirmation and/or clinical/radiological progression, to start 24 weeks (approx. 6 months) TB treatment - 2HRZE/4HR (control-F).
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
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged ≥16 years old on day of randomisation
- •≥25kg in weight on day of randomisation
- •Participation in community or facility-based active case finding for TB by CXR
- •Digital CXR with Computer Aided Detection software score above threshold for sputum investigation for Mtb according to local guidance ≤21 days prior to randomisation
- •Attempted sputum collection for testing by WHO approved rapid molecular test for Mtb at active case finding and at screening
排除标准
- •Sputum sample from active case finding or screening confirmed as positive for Mtb by WHO approved rapid molecular test for Mtb
- •Previous history of pulmonary TB
- •TB preventive therapy taken within the last 6 months
- •>1 dose of treatment with anti-tuberculous activity taken in the 21 days prior to randomisation
- •HIV infected, unless CD4 ≥200 cells/mm3 and on anti-retroviral therapy for at least 8 weeks
- •Pregnancy (confirmed by high sensitivity urine test)
- •Contraindication to study drug
- •Investigator concern for potential extra-pulmonary TB with the exceptions of (a) intrathoracic lymphadenopathy; and/or (b) small pleural effusion of limited extent, neither felt to require invasive diagnostic sampling
- •CXR changes considered more likely to relate to a condition other than untreated TB by investigator
- •Investigator assessment of an immediate requirement for full 24-weeks standard TB treatment
- •Investigator assessment of unacceptable risks to potential participant from study entry
- •No fixed home address
- •Unable to participate in the full duration of study follow-up
研究组 & 干预措施
Arm E. Immediate start of 8 weeks (approx. 2 months) TB treatment
Immediate start of 8 weeks (approx. 2 months) TB treatment comprised of isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE)
干预措施: Isoniazid (H) (Drug)
Arm A. Immediate start of 24 weeks (approx. 6 months) TB treatment
Immediate start of 24 weeks (approx. 6 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 16 weeks (approx. 4 months) of isoniazid and rifampicin (4HR) - 2HRZE/4HR
干预措施: Isoniazid (H) (Drug)
Arm A. Immediate start of 24 weeks (approx. 6 months) TB treatment
Immediate start of 24 weeks (approx. 6 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 16 weeks (approx. 4 months) of isoniazid and rifampicin (4HR) - 2HRZE/4HR
干预措施: Rifampicin (R) (Drug)
Arm A. Immediate start of 24 weeks (approx. 6 months) TB treatment
Immediate start of 24 weeks (approx. 6 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 16 weeks (approx. 4 months) of isoniazid and rifampicin (4HR) - 2HRZE/4HR
干预措施: Pyrazinamide (Z) (Drug)
Arm A. Immediate start of 24 weeks (approx. 6 months) TB treatment
Immediate start of 24 weeks (approx. 6 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 16 weeks (approx. 4 months) of isoniazid and rifampicin (4HR) - 2HRZE/4HR
干预措施: Ethambutol (E) (Drug)
Arm B. Immediate start of 20 weeks (approx. 5 months) TB treatment
Immediate start of 20 weeks (approx. 5 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 12 weeks (approx. 3 months) of isoniazid and rifampicin (3HR) - 2HRZE/3HR
干预措施: Isoniazid (H) (Drug)
Arm B. Immediate start of 20 weeks (approx. 5 months) TB treatment
Immediate start of 20 weeks (approx. 5 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 12 weeks (approx. 3 months) of isoniazid and rifampicin (3HR) - 2HRZE/3HR
干预措施: Rifampicin (R) (Drug)
Arm B. Immediate start of 20 weeks (approx. 5 months) TB treatment
Immediate start of 20 weeks (approx. 5 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 12 weeks (approx. 3 months) of isoniazid and rifampicin (3HR) - 2HRZE/3HR
干预措施: Pyrazinamide (Z) (Drug)
Arm B. Immediate start of 20 weeks (approx. 5 months) TB treatment
Immediate start of 20 weeks (approx. 5 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 12 weeks (approx. 3 months) of isoniazid and rifampicin (3HR) - 2HRZE/3HR
干预措施: Ethambutol (E) (Drug)
Arm C. Immediate start of 16 weeks (approx. 4 months) TB treatment
Immediate start of 16 weeks (approx. 4 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 8 weeks (approx. 2 months) of isoniazid and rifampicin (2HR) - 2HRZE/2HR
干预措施: Isoniazid (H) (Drug)
Arm C. Immediate start of 16 weeks (approx. 4 months) TB treatment
Immediate start of 16 weeks (approx. 4 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 8 weeks (approx. 2 months) of isoniazid and rifampicin (2HR) - 2HRZE/2HR
干预措施: Rifampicin (R) (Drug)
Arm C. Immediate start of 16 weeks (approx. 4 months) TB treatment
Immediate start of 16 weeks (approx. 4 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 8 weeks (approx. 2 months) of isoniazid and rifampicin (2HR) - 2HRZE/2HR
干预措施: Pyrazinamide (Z) (Drug)
Arm C. Immediate start of 16 weeks (approx. 4 months) TB treatment
Immediate start of 16 weeks (approx. 4 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 8 weeks (approx. 2 months) of isoniazid and rifampicin (2HR) - 2HRZE/2HR
干预措施: Ethambutol (E) (Drug)
Arm D. Immediate start of 12 weeks (approx. 3 months) TB treatment
Immediate start of 12 weeks (approx. 6 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 4 weeks (approx. 1 month) of isoniazid and rifampicin (1HR) - 2HRZE/1HR
干预措施: Isoniazid (H) (Drug)
Arm D. Immediate start of 12 weeks (approx. 3 months) TB treatment
Immediate start of 12 weeks (approx. 6 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 4 weeks (approx. 1 month) of isoniazid and rifampicin (1HR) - 2HRZE/1HR
干预措施: Rifampicin (R) (Drug)
Arm D. Immediate start of 12 weeks (approx. 3 months) TB treatment
Immediate start of 12 weeks (approx. 6 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 4 weeks (approx. 1 month) of isoniazid and rifampicin (1HR) - 2HRZE/1HR
干预措施: Pyrazinamide (Z) (Drug)
Arm D. Immediate start of 12 weeks (approx. 3 months) TB treatment
Immediate start of 12 weeks (approx. 6 months) TB treatment comprised of 8 weeks (approx. 2 months) isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE) followed by 4 weeks (approx. 1 month) of isoniazid and rifampicin (1HR) - 2HRZE/1HR
干预措施: Ethambutol (E) (Drug)
Arm E. Immediate start of 8 weeks (approx. 2 months) TB treatment
Immediate start of 8 weeks (approx. 2 months) TB treatment comprised of isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE)
干预措施: Rifampicin (R) (Drug)
Arm E. Immediate start of 8 weeks (approx. 2 months) TB treatment
Immediate start of 8 weeks (approx. 2 months) TB treatment comprised of isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE)
干预措施: Pyrazinamide (Z) (Drug)
Arm E. Immediate start of 8 weeks (approx. 2 months) TB treatment
Immediate start of 8 weeks (approx. 2 months) TB treatment comprised of isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE)
干预措施: Ethambutol (E) (Drug)
结局指标
主要结局
Proportion of participants with an unfavourable TB outcome
时间窗: Over 78 weeks post-randomisation
Unfavourable outcome = requiring initiation of TB treatment after the week 0 visit for either bacteriologically confirmed TB or clinical/radiological progression without bacteriological confirmation
次要结局
- Time to (re-)treatment(Over 78 weeks post-randomisation)
- Proportion of participants with bacteriological confirmation for Mtb(Over 78 weeks post-randomisation)
- Proportion of participants initiated on TB treatment for symptomatic TB(Over 78 weeks post-randomisation)
- Computer Aided Detection (CAD) software score (TB related)(At weeks 8, 36 and 72)
- Forced expiratory volume in 1 second (FEV1)(At 72 weeks)
- Forced vital capacity (FVC)(At 72 weeks)
- FEV1/FVC ratio(At 72 weeks)
- Total time on TB treatment(Over 78 weeks)
- Number Needed to Treat to prevent unfavourable outcome(Over 78 weeks)
- All-cause mortality(Over 78 weeks)
- Proportion of participants experiencing Grade 2/3/4 Adverse Events (AE) (and the subset which are treatment emergent) according to DAIDS criteria(Over 24 and 78 weeks)
- Proportion of participants experiencing Serious Adverse Events(Over 24 and 78 weeks)
- Proportion of participants experiencing Hepatotoxicity AE of Special Interest(Over 24 and 78 weeks)
- Proportion of participants permanently stopping treatment due to an AE of any grade (AESI)(Over 78 weeks)
- Proportion of participants with final diagnosis of baseline CXR abnormality as non-TB(Over 78 weeks)
- Time to non-TB diagnosis(Over 78 weeks)
- Proportion who develop isoniazid and/or rifampicin resistant TB(Over 78 weeks)
- EuroQol Visual Analogue Scale score(Over 72 weeks)
- Short Form 36 (SF-36) score(At weeks 0, 8, 16, 24, 48, 72)
- Chronic Obstructive Pulmonary Disease Assessment Test (CAT) score(At 72 weeks)