A Confirmatory Trial of Adjunctive NAC to Prevent Post Tuberculosis Lung Disease

Официальное название

A Confirmatory Trial of Adjunctive N-acetylcysteine to Prevent Post Tuberculosis Lung Disease (NAC-PTLD) - A TB SEQUEL II Substudy

Обзор

The goal of this clinical trial is to evaluate if N-acetylcysteine (NAC) works to prevent post-tuberculosis lung disease (PTLD) in patients with severe pulmonary impairment. It also aims to assess the safety of NAC. The main questions the study aims to answer are: Does NAC improve lung function (FEV1%) over 12 months in participants with pulmonary tuberculosis and baseline risk factors for PTLD? What medical issues or adverse events do participants experience while taking NAC? Researchers will compare NAC treatment to a control group to see if it can prevent PTLD when given in addition to standard TB treatment. Participants will: Take NAC (1800mg twice daily) for 6 months with standard TB treatment or receive standard TB treatment alone; Attend scheduled clinic visits for 12 months, during which they will have respiratory assessments, blood tests, and symptom monitoring; Complete quality-of-life questionnaires and provide sputum and blood samples for analysis at multiple time points.

Подробное описание

Study Summary: This prospective, randomized, controlled, parallel-arm, open-label clinical trial evaluates the efficacy of N-acetylcysteine (NAC) as an adjunctive therapy for persons with pulmonary tuberculosis and risk factors for PTLD. The study aims to determine the long-term impact of NAC on lung function, respiratory symptoms, and quality of life in patients with drug-sensitive, culture-confirmed pulmonary tuberculosis (TB).

Study Rationale: Pulmonary TB is a leading cause of chronic lung impairment globally. PTLD results in significant morbidity even after successful TB treatment. Prior research suggests NAC may mitigate oxidative stress and preserve lung function in TB patients. This trial seeks to confirm and expand findings from the NAC-TB sub-study of TB Sequel regarding PTLD prevention and treatment.

This trial aims to provide robust evidence on the role of NAC in PTLD management, potentially informing future TB treatment guidelines.

Вмешательства

• Препарат N-Acetyl Cysteine (NAC)
  NAC will be provided as 600 mg capsules from NOW Healthgroup. Standard TB treatment will be provided as fixed dose combination tablets.
• Препарат Standard TB treatment
  Standard TB treatment will be provided as fixed dose combination tablets.

Первичные конечные точки

• FEV1% of predicted at month 12 [Срок оценки: month 12]

Вторичные конечные точки (12)

• FEV1% [Срок оценки: Through study completion, an average of 12 months]
• FVC% [Срок оценки: Through study completion, an average of 12 months]
• FEV/FVC [Срок оценки: Through study completion, an average of 12 months]
• Exacerbations [Срок оценки: Through study completion, an average of 12 months]
• Respiratory QoL at multiple time points [Срок оценки: Through study completion, an average of 12 months]
• Respiratory symptoms [Срок оценки: Through study completion, an average of 12 months]
• Whole blood total glutathione [Срок оценки: Through study completion, an average of 12 months]
• Mtb sputum culture [Срок оценки: Month 2, 3 and 6]
• Change in MGIT (Mycobacterial Growth Indicator Tube) time to positivity (TTP): assessed over time through repeated measurements [Срок оценки: Through study completion, an average of 12 months]
• Treatment failure [Срок оценки: Through study completion, an average of 12 months]
• TB recurrence [Срок оценки: Through study completion, an average of 12 months]
• Number and severity of hepatic safety events [Срок оценки: Through study completion, an average of 12 months]

Критерии участия

Критерии включения

• Persons aged 18 to 65 years
• Willing and able to provide signed written consent, or witnessed oral con-sent with thumbprint in the case of illiteracy, prior to undertaking any trial-related procedures.
• Body weight (in light clothing without shoes) between 30 and 90 kg.
• Xpert TB/RIF OR Ultra showing RIF-S-MTB, with subsequent confirmation of MTB by culture.
• Chest radiograph meeting criteria for moderate or far advanced pulmonary tuberculosis 1
• FEV1 ≤65% of predicted adjusted for age, height, sex, and race
• If female, of child-bearing potential and sexually active, willing to use a contraceptive method for the duration of study participation
• HIV-1/2 seronegative, or if seropositive: CD4 T cell count ≥100/mcL and either currently receiving ART or willing to start ART during study participation

Критерии исключения

• 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, such as pneumothorax or clinically significant pleural effusion
• Pregnancy or breast-feeding
• 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 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, including known allergy or suspected hypersensitivity to rifampin.
• Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial.
• No more than 5 days treatment for the current TB episode, and no other TB treatment in the preceding 6 months
• 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
• Random blood glucose >140 mg/dL (or >7.8 mmol/L), or history of unstable Diabetes Mellitus which required hospitalization for hyper- or hypoglycaemia within the past year prior to start of screening.
• Use of systemic corticosteroids within the past 28 days, or a likely to require corticosteroids for management of another medical condition during the period of study participation.
• Patients requiring treatment with medications not compatible with rifampin, such as HIV protease inhibitors
• Subjects with any of the following abnormal laboratory values:

• creatinine >2 mg/dL
• haemoglobin <8 g/dL
• platelets <100x109 cells/L
• serum potassium <3.5
• aspartate aminotransferase (AST) ≥2.0 x ULN
• alkaline phosphatase (AP) >5.0 x ULN
• total bilirubin >1.5 mg/dL
• positive HBsAg

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Профилактика

Центры проведения

The Gambia · 1 центр

• MRC Unit The Gambia at LSHTM — Fajara

Публикации

• Wallis RS, Sabi I, Lalashowi J, Bakuli A, Mapamba D, Olomi W, Siyame E, Ngaraguza B, Chimbe O, Charalambous S, Rachow A, Ivanova O, Zurba L, Myombe B, Kunambi R, Hoelscher M, Ntinginya N, Churchyard G. Adjunctive N-Acetylcysteine and Lung Function in Pulmonary Tuberculosis. NEJM Evid. 2024 Sep;3(9):EVIDoa2300332. doi: 10.1056/EVIDoa2300332. Epub 2024 Aug 27. PMID 39189858

Идентификаторы

NCT: NCT06909799 · AUR1-1-420

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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