Doxycycline Host-directed Therapy to Improve Lung Function and Decrease Tissue Destruction in Pulmonary Tuberculosis
- Registration Number
- NCT05473520
- Lead Sponsor
- National University Hospital, Singapore
- Brief Summary
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
1. To assess for 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, suppress inflammatory markers including matrix metalloproteinases and accelerate time to sputum culture conversion.
3. To assess the safety profile of doxycycline with concurrent standard anti-tuberculous treatment.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 150
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo + standard anti-tuberculous treatment Placebo 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. Doxycycline + standard anti-tuberculous treatment Doxycycline 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
- Primary Outcome Measures
Name Time Method Forced expiratory volume in 1 second (FEV1) at 26 weeks measured by spirometry week 0 to 26 - 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
- Secondary Outcome Measures
Name Time Method Sputum TB culture up to 8 weeks Time taken in days for positivity of sputum TB culture using MGIT will be assessed
Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC ratio) at 26 weeks Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC ratio) measured by spirometry
Sputum matrix metalloproteinase (MMP) concentration up to 8 weeks Change of sputum matrix metalloproteinase (MMP) concentration will be measured by Luminex array
Pharmacokinetics and pharmacodynamics of drug concentrations week 2 Sputum and plasma drug concentration of rifampicin, isoniazid, ethambutol, pyrazinamide (if prescribed) and doxycycline for a subset PK/PD study
Safety profile week 0 to 26 Incidence of Grade 3 or 4 adverse events and serious adverse events
Cumulative lung cavity volume week 0 to 26 Change in cumulative lung cavity volume (in cm3) measured on CT scan
Resolution of pulmonary cavities on CT scan at 26 weeks Proportion of patients in each study group with resolution of pulmonary cavities on CT scan done at 26 weeks
St George's Respiratory Questionnaire Score week 0 to 26 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.
Sputum culture conversion up to 8 weeks Time taken for sputum culture conversion (time taken for sputum cultures to turn negative) by liquid cultures will be investigated
Sputum functional assays up to 8 weeks Change in sputum functional assays by sputum collagenase and elastase assay will be assessed.
Host plasma matrix metalloproteinase (MMP) concentration week 0 to 26 Change in host plasma matrix metalloproteinase (MMP) concentration will be measured by Luminex array
Host transcriptome week 0 to 26 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.
Trial Locations
- Locations (4)
Hospital Queen Elizabeth I
🇲🇾Kota Kinabalu, Sabah, Malaysia
Universiti Malaysia Sabah (UMS), Borneo Medical and Health Research Centre
🇲🇾Kota Kinabalu, Sabah, Malaysia
National University Hospital
🇸🇬Singapore, Singapore
TB Control Unit
🇸🇬Singapore, Singapore