Test to Treat TB: Impact of Sputum Sequencing-guided Individualised Therapy on Outcomes in Drug-resistant Tuberculosis (TB): a Proof of Concept Randomized Controlled Trial
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 280
- 试验地点
- 1
- 主要终点
- Impact of targeted genome sequencing to initiate more than or equal to five effective TB drugs within 14 days of diagnosis (reference standard phenotypic DST).
研究概览
简要总结
Resistance to anti-tuberculosis drugs is a continually growing problem. Multidrug-resistant tuberculosis (MDRTB) is resistance to at least rifampicin and isoniazid, and extensively drug-resistant TB is additional resistance to a fluoroquinolone and a second injectable line drug. Methods currently employed in testing for resistance are inadequate and a contributing factor to the 40-50% MDR-TB treatment success rate. Current drug susceptibility testing methods are slow for most drugs, taking weeks. Rapid molecular methods such as the line probe assays, e.g. Hain GenoType MDRTBplus and sl, provide resistant calls to only a limited number of drugs, and are often less useful in smear negative patients.
Molecular technologies such as sequencing can provide a comprehensive readout of drug resistance and are able to detect resistant populations at very low levels (≤1%), thus enabling individualized therapy. This can be done directly from sputum. Targeted sequencing amplifies regions of genomic DNA associated with resistance prior to sequencing. Rapid analytic software is used to process the raw sequence data, identify resistance causing mutations and provide a readout of clinically relevant information. However, the feasibility, and more importantly the impact, of this approach has not been evaluated in a clinical trial to establish proof of concept.
Aim 1: To conduct a randomised controlled trial to determine the impact of sputum-based targeted sequencing in detecting resistance to second-line TB drugs compared to the current programmatic standard of care (Hain MDRTBplus/sl and adjunct phenotypic drug susceptibility testing) when used to inform of treatment for MDR-TB.
Aim 2: To compare currently available drug resistant sequencing pipelines for diagnostic accuracy, sensitivity, specificity and predictive value as compared to culture based phenotypic drug susceptibility testing.
Aim 3: To compare the feasibility, accuracy, turn-aroundtime, and cost implications of the above-mentioned diagnostic approaches.
详细描述
Trial aims:
Aim 1: To conduct a randomised controlled trial to determine the impact of sputum-based targeted sequencing in detecting resistance to second-line TB drugs compared to the current programmatic standard of care (Hain MDRTBplus/sl and adjunct phenotypic drug susceptibility testing) when used to inform of treatment for MDR-TB.
Sub-aim 1.1: To determine the proportion of patients (in the control and conventional groups) placed on ≥ 5 likely effective drugs within 14 days of rifampicin resistant tuberculosis diagnosis (the current WHO guideline) in the two groups (targeted sequencing versus LPA and phenotypic testing).
Sub-aim 1.2: To determine time-specific treatment-related outcomes (6, 12, and 18-20 month favourable outcome rates), amplification of drug resistance rates (number of drugs), and 6-month change in chest radiograph disease scores in the two groups.
Sub-aim 1.3: To determine the prevalence of minority hetero-resistant bacterial populations in patients in the same two groups and the change in these populations during the course of treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 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
- •Subjects are required to meet ALL of the following inclusion criteria to participate:
- •Newly diagnosed culture and/or Xpert/MTB Ultra positive pulmonary TB
- •Rifampicin resistance detected using GeneXpert
- •Provide written informed consent prior to all trial-related procedures
- •Male or female aged 18 years and older.
- •Patients on TB treatment for less than or equal to 7 days.
- •Patients receiving both the shorter and longer MDR-TB regimen will be eligible.
排除标准
- •Subjects will be excluded from participation if they meet ANY of the following criteria:
- •A subject who in the opinion of the investigator is unlikely to cope with regular visits to the trial site either because of travel constraints, or drug or alcohol abuse, or other reason.
- •Currently on MDR-TB treatment and completed 7 days of treatment.
- •Any participant with a clinically significant pre-existing medical condition that, in the opinion of the investigator, may be significantly worsened by the patient's participation in the study
- •Any subject with a Karnofsky score <
- •Having participated in other clinical studies within 8 weeks prior to trial start where investigational agents were used that may potentially impact current trial outcome.
- •Participant who is pregnant, breast-feeding (and not willing to stop), or planning to conceive a child within 6 months of cessation of treatment.
- •Any pre-existing laboratory abnormality, which in the opinion of the investigator will place the participant at risk (see detailed protocol for grade of abnormality).
研究组 & 干预措施
Programmatic MDR TB treatment regimen
Conventional MDR-TB laboratory tests. Sputum culture (and smear microscopy) will be evaluated monthly during the treatment period (and 6 monthly during the follow-up period) for the conventional arm.
Sequence based resistance testing and individualized treatment
Sputum extracted for targeted sequencing and drug resistance profile provided to clinician for individualized treatment.
干预措施: Targeted sequencing using the GenoScreen Deeplex assay (Diagnostic Test)
结局指标
主要结局
Impact of targeted genome sequencing to initiate more than or equal to five effective TB drugs within 14 days of diagnosis (reference standard phenotypic DST).
时间窗: 14 days
Impact of sputum-based targeted sequencing in detecting resistance to second-line TB drugs using the GenoScreen Deeplex assay compared to the current programmatic standard of care (Hain MDRTBplus/sl and adjunct phenotypic drug susceptibility testing) when used to inform of treatment for MDR-TB.
次要结局
- Feasibility of targeted sequencing to initiate more than or equal to five effective TB drugs within 14 days of diagnosis.(14 days)
研究者
Keertan Dheda
Professor
University of Cape Town