The goal of this clinical trial is to assess the efficacy(effectiveness) of doxycycline, a potent inhibitor of matrix metalloproteinase (lung collagenase) activity in prevention of Tuberculosis associated lung fibrosis and associated lung function decline among patients with drug sensitive advanced TB. The main question\[s\] it aims to answer are:
* Does doxycycline have a significant anti-fibrosis role when given as adjuvant therapy to TB patients with advanced pulmonary TB in a double blind randomized placebo controlled trial? * How does long term respiratory function defer between patients who received adjuvant doxycycline aimed at prevention of TB associated lung fibrosis and those who received a placebo in a double blind randomized controlled trial?
Participants will be subjected to the following:
* Experimental arm: Doxycycline 100 mg once daily for 12 weeks administered concurrently with standard of care anti-TBs. * Comparator arm: Placebo once daily for 12 weeks administered concurrently with standard of care anti-TBs.
Age of 18 - 65 years
Index PTB episode (sputum smear positive or GeneXpert positive with rifampicin susceptibility)
Baseline CXR showing infiltrates in at least 2 lung zones (≥30% lung involvement) meeting criteria for moderate/advanced PTB
HIV uninfected
Pregnancy
Breastfeeding
Baseline serum creatinine or liver enzymes >2 times above upper limit of normal
Taking corticosteroids for ≥14 days or anti-TBs >7days
Parallel
Doxycycline
DrugDoxycycline is a bacteriostatic tetracycline antibiotic with ability to immunomodulate matrix metalloproteinases, enzymes well known to cause lung damage via breakdown lung extracellular matrix.
Placebo
DrugThis will be a chemically inert substance, designed to match oral doxycycline capsules but with no chemically active ingredients.
Mean High resolution CT (HRCT) fibrosis scores
Quantified fibrosis scores (e.g. 0 - 25) will be derived from the CT interpretation tool, and recorded for each participant at baseline and 12 months' HRCT images, and compiled per treatment arm. Mean scores per study arm (intervention and control) will de determined for both baseline and 12 months' HRCT scans.
Efficacy of doxycycline as an anti-TB associated fibrosis agent
This will be estimated or analyzed using analysis of covariance method. The difference in the mean 'total HRCT fibrosis score' between the intervention and control study arms shall be compared at 12 months adjusting for the total scores measured at baseline. A linear regression model shall be fit on log transformed values of total HRCT scores for each individual.
Lung function assessment
Lung volumes including Forced expiratory volume in 1 second (FEV1), Forced vital capacity(FVC) will be obtained at spirometry for all subjects in both study arms (doxycycline and placebo) and compared with predicted values (standardized values for age, sex, race and smoking status) and results (percentage of predicted) compared across both study groups at 6 and 12 months.
Correlation between the High-Resolution CT fibrosis score and lung function assessment
TB associated fibrosis will be quantified on CT using total scores derived a modified and adapted version of the Bhalla CT interpretation score for HRCTs done at baseline and 12 months. Lung function assessment will be by spirometry and will be derived as percentage predicted values of participants' lung volumes (FEV1, FVC) at 6 and 12 months and age, sex, race and smoking status standardized values. To estimate the correlation between the HRCT fibrosis score and the lung function assessment in each study arm (Doxycycline versus placebo); 3 log linear models shall be fit. These will include: * Log linear model of interaction between FEV1 and treatment arm * Log linear model of interaction between FVC and treatment arm * Log linear model of interaction between FEV1/FVC ratio and treatment arm
comparison of trends of cytokines (matrix metalloproteinases and TGF beta) between intervention and control arm
Serum concentrations of matrix metalloproteinases (MMPs 1, 3, 8, 9) and Transforming growth factor beta 1 (TGFβ1) will be measured in ng/ml at baseline, 3 and 6 months. Means of the MMP concentrations will be calculated and compared between intervention and placebo arm (at baseline, 3 and 6 months) and analyzed using repeated analysis of variance and mixed effect model.
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Makerere University
Lead sponsor
Makerere University Lung Institute
Collaborator
