Doxycycline Host-directed Therapy to Improve Lung Function and Decrease Tissue Destruction in Pulmonary Tuberculosis

Study Overview
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Brief Summary
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Tuberculosis (TB) is a global pandemic that despite successful treatment and bacterial eradication can cause chronic ill health, also known as pulmonary impairment after tuberculosis (PIAT). A recent Phase 2b double-blind randomised-controlled clinical trial shows that adjunctive doxycycline therapy along with standard pulmonary TB (PTB) treatment is safe, accelerates resolution of inflammation, suppresses tissue damaging enzyme activity and decreases pulmonary cavity volume (1). The investigators aim to determine if adjunctive doxycycline can reduce PIAT in a fully powered Phase III trial of 8 weeks of adjunctive doxycycline alongside standard pulmonary TB treatment. The investigators hypothesize that doxycycline inhibits tissue destruction in patients with pulmonary tuberculosis (PTB) and thereby leads to improved lung function after treatment. Specific aims To assess for improvement in lung function as measured by forced expiratory volume (FEV1) predicted in PTB patients given doxycycline versus placebo. To investigate whether doxycycline will hasten the resolution of pulmonary cavities measured by CT thorax, suppress inflammatory markers including matrix metalloproteinases and accelerate time to sputum culture conversion. To assess the safety profile of doxycycline with concurrent standard anti-tuberculous treatment.

Detailed Description
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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 four 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 and non-contrast CT thorax 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. Accomplishing these specific aims will determine if doxycycline decreases PIAT by improving lung function, reducing pulmonary cavities and accelerating sputum culture conversion. 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.

Official Title
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Doxycycline Host-directed Therapy to Improve Lung Function and Decrease Tissue Destruction in Pulmonary Tuberculosis: A Phase III Randomized Control Trial (Doxy-TB)

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Doxycycline
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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The recruitment target would be 150 patients, with 75 in each arm Inclusion criteria: Patients should meet all criteria: Aged 21 years and above Patients receiving ≤ 7 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 Able to provide informed consent Exclusion criteria: HIV co-infection Previous pulmonary TB Severe, pre-existing lung disease such as pulmonary fibrosis, bronchiectasis, COPD and lung cancer Pregnant or breast feeding Allergies to tetracyclines Patients on retinoic acid, neuromuscular blocking agents and pimozide which may increase risk of drug toxicity Autoimmune disease and/or on systemic immunosuppressants 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 Enrolment in any other clinical trial involving a systemic drug or intervention involving the lung Evidence of severe depression, schizophrenia or mania ALT > 3 times upper limit of normal Creatinine > 2 times upper limit of normal 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

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doxycycline + standard anti-tuberculous treatment<br>Doxycycline 100 mg twice daily with once daily anti-tuberculous treatment comprising of rifampicin 10 mg/kg, isoniazid 5 mg/kg, ethambutol 15 - 20 mg/kg, ± pyrazinamide 25 mg/kg and pyridoxine 10-50 mg per day according to managing physicians' discretion. Where needed, the drugs will be adjusted according to renal function. These will be given daily for 8 weeks. Subsequently doxycycline will be ceased and patients are to continue with their standard anti-tuberculous treatment and duration according to their managing physician | Drug: Doxycycline<br>* 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.<br>|
| Placebo Comparator: Placebo + standard anti-tuberculous treatment<br>Placebo twice daily with once daily anti-tuberculous treatment comprising of rifampicin 10 mg/kg, isoniazid 5 mg/kg, ethambutol 15-20 mg/kg, ± pyrazinamide 25 mg/kg and pyridoxine 10-50 mg per day according to managing physicians' discretion. Where needed, the drugs will be adjusted according to renal function. These will be given daily for 8 weeks. Subsequently placebo will be ceased and patients are to continue with their standard anti-tuberculous treatment and duration according to their managing physician. | Drug: Placebo<br>* Placebo + standard anti-tuberculous treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | week 0 to 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | at 26 weeks | 
| Safety profile | Incidence of Grade 3 or 4 adverse events and serious adverse events | week 0 to 26 | 
| 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 weeks | at 26 weeks | 
| Cumulative lung cavity volume | Change in cumulative lung cavity volume (in cm3) measured on CT scan | week 0 to 26 | 
| 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. | week 0 to 26 | 
| Sputum TB culture | Time taken in days for positivity of sputum TB culture using MGIT will be assessed | up to 8 weeks | 
| Sputum culture conversion | Time taken for sputum culture conversion (time taken for sputum cultures to turn negative) by liquid and solid cultures will be investigated | up to 8 weeks | 
| Sputum matrix metalloproteinase (MMP) concentration | Change of sputum matrix metalloproteinase (MMP) concentration will be measured by Luminex array | up to 8 weeks | 
| Sputum functional assays | Change in sputum functional assays by sputum collagenase and elastase assay will be assessed. | 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. | week 0 to 26 | 
| Host plasma matrix metalloproteinase (MMP) concentration | Change in host plasma matrix metalloproteinase (MMP) concentration will be measured by Luminex array | week 0 to 26 | 
| 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 | week 2 |