A Randomized Controlled Trial of 2 Disease-Modifying Drugs (Metformin and N-acetylcysteine ) to Promote TB Lung Function Recovery (TB-MET-NAC)
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 1,104
- 主要终点
- FEV1
研究概览
简要总结
Tuberculosis is a leading global cause of morbidity and mortality. Even if cured, a majority patients are left with bronchiectasis and fibrosis, permanent conditions that impair lung function. Large cohort studies have confirmed that even modest loss of lung function is associated with excess mortality risk. This study will examine if two treatments, metformin and N-acetylcysteine (NAC), can promote the recovery of lung function in TB if given together with standard TB treatment. There currently are no drugs approved for this indication.
详细描述
Tuberculosis is a leading global cause of morbidity and mortality. Current treatments are inadequate, requiring patients closely adhere to multi-drug regimens that are long, complex, and often poorly tolerated and/or ineffective. Even if cured, a majority patients are left with bronchiectasis and fibrosis, permanent conditions that impair lung function, particularly causing loss of FEV1% (the maximal 1-second exhaled volume in relation to age, sex, and height). FEV1 loss has profound long-term health consequences. Large cohort studies have confirmed that even modest loss of FEV1, remaining within 'normal' limits, is associated with excess mortality risk. This is most pronounced in low-income countries where TB is most prevalent. This study will examine if two treatments, metformin and N-acetylcysteine (NAC), can promote the recovery of lung function in TB. There currently are no drugs approved for this indication.
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
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Willing and able to provide signed written consent (or, in the case of illiteracy, witnessed oral consent plus patient thumbprint) prior to undertaking any trial-related procedures.
- •Body weight (in light clothing without shoes) between 30 and 90 kg.
- •Radiographic evidence of pulmonary tuberculosis
- •Positive Xpert TB/RIF (original or Ultra) for MTB
- •RIF susceptibility diagnosed by Xpert TB/RIF, with subsequent culture confirmation
- •FEV1≤65% of predicted
- •Eligible for treatment with a 6-month regimen comprised of INH, RIF, EMB, and PZA
- •If sexually active, willing to use effective contraceptive methods for a period of 9 months (3 months post-study treatment)
- •HIV-1 seronegative, or if HIV-1 seropositive, presenting to a non-India clinical site with a CD4 T cell count ≥100/µl and either receiving ART or willing to start ART during study participation
- •SARS-CoV-2 PCR or antigen test negative, or if positive, either fully vaccinated against Covid-19 or with D-dimer <1 µg/ml
- •eGFR ≥30 ml/min/1.73 m2 (CKD EPI 2009)
排除标准
- •Any condition for which participation in the trial, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments
- •Currently pregnant or nursing, or pregnancy planned in next 12 months
- •Is critically ill, and in the judgment of the investigator has a diagnosis likely to result in death during the trial or the follow-up period.
- •TB meningitis or spondylitis, or other forms of severe tuberculosis with high risk of a poor outcome as judged by the investigator.
- •History of allergy or hypersensitivity to any of the trial therapies or related substances.
- •History of a chronic lung condition (including COPD or asthma) requiring treatment in the previous year
- •Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial.
- •Prior TB treatment in the preceding 6 months, other than within the 7 days immediately prior to enrollment.
- •Angina pectoris requiring treatment with nitroglycerin or other nitrates
- •Cardiac arrhythmia requiring medication, or any clinically significant ECG abnormality, in the opinion of the investigator
- •History of diabetes mellitus requiring treatment with metformin or resulting in hospitalization for hyper- or hypoglycaemia within the past year prior to start of screening
- •Use of systemic corticosteroids within the past 28 days.
- •Patients requiring treatment with medications not compatible with rifampin, such as HIV-1 protease inhibitors
- •History of Pneumoconiosis.
- •Subjects with any of the following abnormal laboratory values: hemoglobin <8 g/dL, platelets <100x109 cells/L, serum potassium <3.5 mM/L, alanine aminotransferase (ALT) ≥2.0 x ULN, alkaline phosphatase (AP) >5.0 x ULN, total bilirubin >1.5 mg/dL, HbA1c >6.5 %
研究组 & 干预措施
Metformin plus SOC
Metformin 1500 mg total daily for 6 months plus standard TB treatment
干预措施: Metformin (Drug)
N-acetylcysteine (NAC) plus SOC
NAC 3600 mg total daily for 6 months plus standard TB treatment
干预措施: N-Acetylcysteine (NAC) Treatment (Dietary Supplement)
Control (SOC)
Standard TB treatment alone
干预措施: Standard TB treatment (Combination Product)
结局指标
主要结局
FEV1
时间窗: month 18
FEV1 after adjustment for baseline covariates including FEV1, in a superiority comparison
Favourable treatment outcome
时间窗: 18 months
Proportion of participants achieving a favourable treatment outcome (other than death, failure, recurrence, loss, default) in a non-inferiority comparison
次要结局
- Radiography(18 months)
- Other measures of lung function(Through month 18)
- Microbiology(Through month 6)
- Serious and non-serious adverse events(Through month 18)
- Pharmacology(After 1 month of TB treatment)
- Immunology(2, 6, and 18 months)