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.

The recruitment target would be 150 patients, with 75 in each arm

Inclusion criteria: Patients should meet all criteria:

1. Aged 21 years and above
2. Patients receiving ≤ 14 days of TB treatment or about to start standard combination TB treatment
3. Confirmed pulmonary TB with positive acid-fast bacilli smear and/or positive nucleic acid amplification test (NAAT) and/or TB culture results
4. CXR demonstrating pulmonary involvement with cavity or cavities
5. Able to provide informed consent

Exclusion criteria:

1. HIV co-infection
2. Previous pulmonary TB
3. Severe, pre-existing lung disease such as pulmonary fibrosis, bronchiectasis, COPD and lung cancer
4. Pregnant or breast feeding
5. Allergies to tetracyclines
6. Patients on retinoic acid, neuromuscular blocking agents and pimozide which may increase risk of drug toxicity
7. Autoimmune disease and/or on systemic immunosuppressants
8. Use of any investigational or non-registered drug, vaccine or medical device other than the study drug within 182 days preceding dosing of study drug, or planned use during the study period
9. Enrolment in any other clinical trial involving a systemic drug or intervention involving the lung
10. Evidence of severe depression, schizophrenia or mania
11. ALT > 3 times upper limit of normal
12. Creatinine > 2 times upper limit of normal
13. Principal investigator assessment of lack of willingness to participate and comply with all requirements including follow-up of the protocol, or identification of any factor felt to significantly increase the participant's risk of suffering an adverse outcome