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.
Aged 21 years and above
Patients receiving ≤ 14 days of TB treatment or about to start standard combination TB treatment
Confirmed pulmonary TB with positive acid-fast bacilli smear and/or positive nucleic acid amplification test (NAAT) and/or TB culture results
CXR demonstrating pulmonary involvement with cavity or cavities
HIV co-infection
Previous pulmonary TB
Severe, pre-existing lung disease such as pulmonary fibrosis, bronchiectasis, COPD and lung cancer
Pregnant or breast feeding
Parallel
Doxycycline
DrugA 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
DrugPlacebo + standard anti-tuberculous treatment
Forced 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
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.
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
Safety profile
Incidence of Grade 3 or 4 adverse events and serious adverse events
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
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National University Hospital, Singapore
Lead sponsor
Tan Tock Seng Hospital
Collaborator
Hospital Queen Elizabeth, Malaysia
Collaborator
National University of Singapore
Collaborator
University Malaysia Sabah
Collaborator
Menggatal Health Clinic, Sabah, Malaysia
Collaborator
Luyang Health Clinic, Sabah, Malaysia
Collaborator
