Tuberculosis (TB) is a global pandemic that despite successful treatment and bacterial eradication can cause chronic ill health, such as pulmonary impairment after tuberculosis (PIAT) and cardiovascular disease (CVD). A recent Phase 2b double-blind randomised-controlled clinical trial shows that adjunctive doxycycline therapy is safe, accelerates resolution of inflammation, suppresses tissue damaging enzyme activity and decreases pulmonary cavity volume (1). We aim to determine if adjunctive doxycycline can reduce PIAT and improve cardiovascular outcomes in a fully powered Phase III trial of 8 weeks of adjunctive doxycycline alongside standard pulmonary TB (PTB) treatment. The investigators hypothesize that doxycycline inhibits tissue destruction in patients with PTB and thereby leads to improved lung function after treatment. Specific aims 1. To assess improvement in lung function as measured by forced expiratory volume (FEV1) predicted in PTB patients given doxycycline versus placebo. 2. To investigate whether doxycycline will hasten the resolution of pulmonary cavities measured by CT thorax 3. To investigate whether doxycycline can suppress inflammatory markers including matrix metalloproteinases 4. To investigate whether doxycycline can accelerate time to sputum conversion 5. To evaluate the effect of doxycycline on cardiovascular outcomes such as the incidence of acute coronary syndrome (ACS) and pulmonary hypertension 6. To investigate whether doxycycline improves TB drug concentrations in sputum and plasma. 7. To assess the safety profile of doxycycline with concurrent standard anti-tuberculous treatment.
In this Phase 3 double-blind randomised-controlled trial, doxycycline or placebo shall be given to 75 PTB patients in each arm for two months with a further follow-up of twenty-two months. Study sites are National University Hospital and TB Control Unit in Singapore and Luyang Health Clinic, Menggatal Health Clinic, and Inanam Health Clinic in Sabah, Malaysia. Lung function tests, non-contrast CT thorax, electrocardiograms and transthoracic echocardiograms will be performed at various time intervals. Induced sputum and plasma samples from all PTB patients shall be analysed for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and monitored for sputum mycobacteria culture conversion. Whole blood will be analysed by transcriptomics for bulk RNAseq while a subset of patients' blood will be analysed using single-cell RNAsequencing. Blood tests will also be taken for Troponin-I and N-terminal pro-B-type natriuretic peptide. Accomplishing these specific aims will determine if doxycycline decreases PIAT by improving lung function, reducing pulmonary cavities and accelerating sputum culture conversion. We will also be able to assess the effect of doxycycline on development of pulmonary hypertension and acute coronary syndrome. The results will positively impact clinical practice and international guidelines including the World Health Organisation that we collaborate with, for the treatment of pulmonary TB.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
150
A dose of 100 mg twice daily of doxycycline based on the recommended dose for adults which is commonly used for bacterial infections such as rickettsial infection, lyme disease and pelvic inflammatory disease.
Placebo + standard anti-tuberculous treatment
Hospital Queen Elizabeth I
Kota Kinabalu, Sabah, Malaysia
NOT_YET_RECRUITINGKlinik Kesihatan Luyang
Kota Kinabalu, Sabah, Malaysia
ACTIVE_NOT_RECRUITINGKlinik Kesihatan Menggatal
Kota Kinabalu, Sabah, Malaysia
RECRUITINGUniversiti Malaysia Sabah (UMS), Borneo Medical and Health Research Centre
Kota Kinabalu, Sabah, Malaysia
ACTIVE_NOT_RECRUITINGNational University Hospital
Singapore, Singapore, Singapore
RECRUITINGTB Control Unit
Singapore, Singapore
RECRUITINGForced expiratory volume in 1 second (FEV1) at 26 weeks measured by spirometry
\- FEV1 at 26 weeks, expressed as a percentage predicted for age, sex, height and race will be measured by spirometry and will be compared between the doxycycline and placebo group
Time frame: week 0 to 26
Forced expiratory volume in 1 second (FEV1) at 104 weeks measured by spirometry
Forced expiratory volume, expressed as a percentage predicted for age, sex, height and race will be measured by spirometry and will be compared between the doxycycline and placebo group will be measured at D0, week 8, week 26, week 52, week 78 and week 104.
Time frame: 104 weeks
Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC ratio)
Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC ratio) measured by spirometry
Time frame: 104 weeks
Safety profile
Incidence of Grade 3 or 4 adverse events and serious adverse events
Time frame: week 0 to 12
Resolution of pulmonary cavities on CT scan
Proportion of patients in each study group with resolution of pulmonary cavities on CT scan done at 26, 52, 78, 104 weeks
Time frame: 104 weeks
Cumulative lung cavity volume
Change in cumulative lung cavity volume (in cm3) measured on CT scan
Time frame: week 0 to 104
St George's Respiratory Questionnaire Score
Change in Quality-of-life score by the St George's Respiratory Questionnaire will be measured. Scores range from 0 to 100, with higher scores indicating more limitations.
Time frame: week 0 to 104
Sputum TB culture
Time taken in days for positivity of sputum TB culture using MGIT will be assessed
Time frame: up to 8 weeks
Sputum culture conversion
Time taken for sputum culture conversion (time taken for sputum cultures to turn negative) by liquid cultures will be investigated
Time frame: up to 8 weeks
Sputum matrix metalloproteinase (MMP) concentration
Change of sputum matrix metalloproteinase (MMP) concentration will be measured by Luminex array
Time frame: up to 8 weeks
Sputum functional assays
Change in sputum functional assays by sputum collagenase and elastase assay will be assessed.
Time frame: up to 8 weeks
Host transcriptome
Change of host transcriptome will be measured via bulk RNA sequencing. In addition, in the subset of patients recruited from Singapore, single-cell RNA sequencing (scRNAseq) will be performed for neutrophils and peripheral blood mononuclear cells on 10 patients each from the doxycycline and placebo arm, analysing 10,000 cells per sample.
Time frame: week 0 to 104
Host plasma matrix metalloproteinase (MMP) concentration
Change in host plasma matrix metalloproteinase (MMP) concentration will be measured by Luminex array
Time frame: week 0 to 104
Pharmacokinetics and pharmacodynamics of drug concentrations
Sputum and plasma drug concentration of rifampicin, isoniazid, ethambutol, pyrazinamide (if prescribed) and doxycycline for a subset PK/PD study
Time frame: week 2
Cardiac function and pulmonary hypertension
Cardiac function and pulmonary artery systolic pressure will be measured using 2D Echocardiogram and electrocardiogram at D0, week 26, week 52, week 78 and week 104. The time-to-development of pulmonary hypertension over 2 years follow-up will be calculated.
Time frame: week 0 to 104
Measurement of Troponin I and NT-proBNP
HsTnI and NT-proBNP will be measured sequentially at Day 0, Week 2, 8, 26, 52, 78 and 104 to screen for cardiotoxicity, which will then be ascertained by review of source documents.
Time frame: week 0 to 104
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