Phase 2b Randomized Double-blind, Placebo-controlled Trial to Estimate the Potential Efficacy and Safety of Two Repurposed Drugs, Acetylsalicylic Acid and Ibuprofen, for Use as Adjunct Therapy Added to, and Compared With, the Standard WHO-recommended TB Regimen (SMA-TB)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 426
- 试验地点
- 6
- 主要终点
- Hazard ratio for time to stable culture conversion (SCC)
研究概览
简要总结
The purpose of this study is to assess the efficacy and safety of 2 repurposed drugs (acetylsalicylic acid and ibuprofen), for use as adjunct therapy added to, and compared with, the standard of care (SoC) WHO-recommended TB regimen in drug-sensitive (DS) and multi-drug resistant (MDR) TB patients.
详细描述
If eligible and informed consent obtained, patients will be randomized 1:1:1 into one of the following 3 arms, to receive:
- Standard of Care (SoC) TB treatment + placebo twice daily during the first 4 weeks of TB treatment followed by placebo once daily for an additional 4 weeks. (control group).
- SoC TB treatment + acetylsalicylic acid 300mg twice daily during the first 4 weeks of TB treatment followed by acetylsalicylic acid 300mg once daily for an additional 4 weeks.
- SoC TB treatment + ibuprofen 400mg twice daily during the first 4 weeks of TB treatment followed by ibuprofen 400mg once daily for an additional 4 weeks.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults, 18- 60 years of age
- •Written informed consent in a language they understand. This includes informed consent to be in the trial and informed consent to collect specimens.
- •Laboratory confirmed pulmonary TB (with or without extrapulmonary involvement) defined as a hard copy of a sputum laboratory result that reports M. tuberculosis (Mtb) detection by a WHO-recommended assay -both rapid molecular assays or mycobacterial culture with subsequent speciation are acceptable as inclusion criteria.
- •Women of childbearing potential (including females <2 years post-menopausal) must have a negative pregnancy test at enrolment.
- •Participants must be willing to have an HIV test done unless there is compelling evidence that the patient is HIV-infected at the time of randomization.
排除标准
- •Has a comorbid condition where treatment with aspirin, ibuprofen or other NSAID is indicated (e.g. cardiovascular disease, rheumatic fever, chronic pain, etc.)
- •People institutionalized (incarceration in jail or prison, or due to chronic mental illness). If incarcerated during the study, participants may be terminated, those incarcerated in the first 8 weeks of follow up will be late exclusions and replaced*. Patients either who are planned to be hospitalized or currently hospitalized whilst treated for MDR TB in a TB hospital or ward may be enrolled.
- •Receipt of multi-drug TB treatment (including rifamycin plus isoniazid preventive treatment regimens) for ≥3 days in the 6 months prior to randomization. Participants who have received ≥3 days of TB preventive treatment in the month prior to TB treatment initiation will also be excluded.
- •Currently Pregnancy/breastfeeding. Women who conceive and are found to be pregnant in the first 4 weeks of the trial will be terminated from the trial and excluded from the analysis.
- •Any of the following laboratory parameters taken prior to randomization:
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN);
- •Total bilirubin > 2 x ULN;
- •Neutrophil count ≤ 700 neutrophils /mm3;
- •Platelet count < 50,000 cells / mm3
- •Haemoglobin concentration less than 8 g/dL
- •Serum creatinine concentration more than twice the upper limit of normal
- •Co-treatment in the three months prior to randomization, or planned treatment over the course of the trial follow up with any one of the following agents:
- •anticoagulant therapy
- •immune modulating therapy (cancer treatments, any oral or daily use of inhaled steroids;
- •Antacids or proton pump inhibitors - including self-treatment and prescription
- •History or clinical record of sensitivity, asthma or allergy that could be attributed to NSAIDs
- •Weight < 45kg at baseline.
- •History or clinical record suggestive of any of the following in the past two years:
- •peptic ulcer disease or gastro-intestinal bleeding,
- •coagulopathy or other bleeding disorder,
- •renal disease requiring hospitalization - in addition, any prior record at any time of acute kidney injury will be an exclusion criterion.
- •liver disease requiring further investigation or hospitalization,
- •underlying cardiovascular disease or risk factors for cardiovascular disease.
- •Patients with HIV infection (irrespective of ART status) if:
- •CD4 <350 cells/mm3
- •if on ART, unsuppressed (>200 copies/ml) viral load
- •if not on ART, either in the opinion of the attending doctor or according to local ART guidelines, the patient should initiate ART during the 8-week initial placebo or NSAID treatment phase.
- •Alcohol use: potential participant either self-reports or in the investigator's opinion that the patient drinks more than an average of four units/day over a usual week or is a binge drinker (men: 5 or more drinks; women: consume 4 or more drinks, in about 2 hours).
- •Major co-morbid conditions or any other finding which in the opinion of the investigator would compromise the protocol compliance or significantly influence the interpretation of results.
研究组 & 干预措施
Control group
Standard of Care (SoC) TB treatment + placebo twice daily during first 4 weeks of TB treatment followed by placebo once daily for an additional 4 weeks.
干预措施: Control group (Drug)
SoC TB + ASA group
Standard of Care (SoC) TB treatment + acetylsalicylic acid 300mg twice daily during first 4 weeks of TB treatment followed by aspirin 300mg once daily for an additional 4 weeks.
干预措施: ASA group (Drug)
SoC TB + IBU group
Standard of Care (SoC) TB treatment + ibuprofen 400mg twice daily during first 4 weeks of TB treatment followed by ibuprofen 400mg once daily for an additional 4 weeks
干预措施: IBU group (Drug)
Control group
Standard of Care (SoC) TB treatment + placebo twice daily during first 4 weeks of TB treatment followed by placebo once daily for an additional 4 weeks.
干预措施: SoC TB (Drug)
SoC TB + ASA group
Standard of Care (SoC) TB treatment + acetylsalicylic acid 300mg twice daily during first 4 weeks of TB treatment followed by aspirin 300mg once daily for an additional 4 weeks.
干预措施: SoC TB (Drug)
SoC TB + IBU group
Standard of Care (SoC) TB treatment + ibuprofen 400mg twice daily during first 4 weeks of TB treatment followed by ibuprofen 400mg once daily for an additional 4 weeks
干预措施: SoC TB (Drug)
结局指标
主要结局
Hazard ratio for time to stable culture conversion (SCC)
时间窗: 24 weeks of TB treatment
Hazard ratio for time to stable culture conversion (SCC), at least 2 consecutive negative cultures for M. tuberculosis at least 4 weeks apart during the first 24 weeks of TB treatment.
Time to ≥ 67% sustained reduction in the TB score
时间窗: Week 8 of follow-up
Time to ≥ 67% sustained reduction in the TB score over the course of TB treatment
次要结局
- Proportion of patients with improvement of lung function impairment as change from baseline at week 8, 24 and end of treatment in the 1-second forced expiratory volume (FEV1) expressed as FEV1.(At baseline, week 8 and week 24)
- Changes in the BCN-SA Radiological Score Value.(At baseline, week 8, week 24 (and month 12 if MDR))
- Number of patients with improvement of Health-related Quality of Life comparing baseline measure with that over the course of therapy.(At week 8, week 24 and for MDR TB patients at the end of treatment)
- Hazard ratio for stable culture conversion (SCC) at week 8 and week 16 after treatment start.(At week 8 and week 16)
- Proportion of patients with improvement or resolution of clinical signs and symptoms at end of treatment (TB score).(At week 24)