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Evaluation of metformin in combination with rifampicin containing antituberculosis therapy in patients with new, smear-positive pulmonary tuberculosis (METRIF): study protocol for a randomised clinical trial.

ABSTRACT: INTRODUCTION:Shorter duration of treatment for the management of drug-susceptible pulmonary tuberculosis (TB) would be a significant improvement in the care of patients suffering from the disease. Besides newer drugs and regimens, other modalities like host-directed therapy are also being suggested to reach this goal. This study's objective is to assess the efficacy and safety of metformin-containing anti-TB treatment (ATT) regimen in comparison to the standard 6-month ATT regimen in the treatment of patients with newly diagnosed sputum smear-positive drug-sensitive pulmonary TB. METHODS AND ANALYSIS:We are conducting a multicentric, randomised open-label controlled clinical trial to achieve the study objective. The intervention group will receive isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) along with 1000 mg of daily metformin (Met) for the first 2 months while the control group will receive only HRZE. After 2 months, both the groups will receive HRE daily for 4 months. The primary endpoint is time to sputum culture conversion. Secondary endpoints will include time to detection of Mycobacterium tuberculosis in sputum, pharmacokinetics and pharmacogenomics of study drugs, drug-drug interactions, safety and tolerability of the various combinations and measurement of autophagy and immune responses in the study participants. ETHICS AND DISSEMINATION:The ethics committee of the participating institutes have approved the study. Results from this trial will contribute to evidence towards constructing a shorter, effective and safe regimen for patients with TB. The results will be shared widely with the National Programme managers, policymakers and stakeholders through open access publications, dissemination meetings, conference abstracts and policy briefs. This is expected to provide a new standard of care for drug-sensitive patients with pulmonary TB who will not only reduce the number of clinic visits and lost to follow-up of patients from treatment but also reduce the burden on the healthcare system. TRIAL REGISTRATION NUMBER:CTRI/2018/01/011176; Pre-results.

SUBMITTER: Padmapriyadarsini C

PROVIDER: S-EPMC6429929 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSputum smear conversion is a key indicator of treatment response and reduced infectivity among bacteriologically confirmed pulmonary tuberculosis (PTB) patients. This study aimed at estimating sputum smear conversion and identifying factors hindering sputum smear conversion among bacteriologically confirmed PTB cases in East Gojjam Zone, Northwest Ethiopia.MethodsA total of 282 bacteriologically confirmed PTB patients were followed for 22 weeks through weekly sputum smear examination. Due to the absence of sputum culture and rapid diagnostic services, sputum smear conversion evaluation was conducted microscopically using acid-fast-bacilli staining technique of sediments from a 5% sodium hypochlorite concentration technique. Data on socio-demographic, clinical profile and personal behavior variables were collected using a pretested interviewer-administered questionnaire. Various descriptive statistics including mean, median with interquartile range (IQR), and proportions were computed to describe study objectives. Factors of sputum smear conversion were identified by multivariable logistic regression analysis and statistical significance was determined at a p value < 0.05.ResultsOver half, 166 (59%) of bacteriologically confirmed PTB patients were males and 147 (52%) were rural dwellers. The mean age of respondents was 35 ± 5 SD years. About 88 (31.2%) of bacteriologically confirmed PTB patients had comorbidities, 102 (36.2%) faced stigma, and 54 (19%) history of cigarette smoking. The median sputum smear conversions during the intensive phase and 5th months of treatment follow up were 35 dyas (IQR: 21-56 days) and 53 days (IQR: 28-82 days), respectuvely. The majority, 85% (95% CI 76-93%) and 95% (95% CI 85-99%) of bacteriologically confirmed PTB patients underwent sputum smear conversion at the end of 2nd and 5th months of treatment, respectively. Poor knowledge on TB, being HIV positive, higher smear grading, having diabetes mellitus, undernutrition, cigarette smoking, facing societal stigma, and TB service delays were positively associated with the length of sputum smear conversion (p value < 0.05).ConclusionBased on this study, the median sputum smear conversion time was higher compared to TB program expectations and findings from former studies. The study also identified important factors associated with sputum smear conversion time. Improving health literacy of the community by revising the existing community awareness strategies is essential to enhance treatment adherence and lower infectiousness after treatment initiation.

Project description:BackgroundChest radiographs are used for diagnosis and severity assessment in tuberculosis (TB). The extent of disease as determined by smear grade and cavitation as a binary measure can predict 2-month smear results, but little has been done to determine whether radiological severity reflects the bacterial burden at diagnosis.MethodsPre-treatment chest x-rays from 1837 participants with smear-positive pulmonary TB enrolled into the REMoxTB trial (Gillespie et al., N Engl J Med 371:1577-87, 2014) were retrospectively reviewed. Two clinicians blinded to clinical details using the Ralph scoring system performed separate readings. An independent reader reviewed discrepant results for quality assessment and cavity presence. Cavitation presence was plotted against time to positivity (TTP) of sputum liquid cultures (MGIT 960). The Wilcoxon rank sum test was performed to calculate the difference in average TTP for these groups. The average lung field affected was compared to log 10 TTP by linear regression. Baseline markers of disease severity and patient characteristics were added in univariable regression analysis against radiological severity and a multivariable regression model was created to explore their relationship.ResultsFor 1354 participants, the median TTP was 117 h (4.88 days), being 26 h longer (95% CI 16-30, p < 0.001) in patients without cavitation compared to those with cavitation. The median percentage of lung-field affected was 18.1% (IQR 11.3-28.8%). For every 10-fold increase in TTP, the area of lung field affected decreased by 11.4%. Multivariable models showed that serum albumin decreased significantly as the percentage of lung field area increased in both those with and without cavitation. In addition, BMI and logged TTP had a small but significant effect in those with cavitation and the number of severe TB symptoms in the non-cavitation group also had a small effect, whilst other factors found to be significant on univariable analysis lost this effect in the model.ConclusionsThe radiological severity of disease on chest x-ray prior to treatment in smear positive pulmonary TB patients is weakly associated with the bacterial burden. When compared against other variables at diagnosis, this effect is lost in those without cavitation. Radiological severity does reflect the overall disease severity in smear positive pulmonary TB, but we suggest that clinicians should be cautious in over-interpreting the significance of radiological disease extent at diagnosis.

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Evaluation of metformin in combination with rifampicin containing antituberculosis therapy in patients with new, smear-positive pulmonary tuberculosis (METRIF): study protocol for a randomised clinical trial.

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