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

Tuberculosis Clinical Trial

— Doxy-TB  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05473520
• Other study ID #: Phase III Doxy-TB
• Status: Recruiting
• Phase: Phase 3
• Start date: May 24, 2023
• Est. completion date: January 27, 2027

Study information

• Verified date: September 2023
• Source: National University Hospital, Singapore
• Contact: Srishti CHHABRA, MBBS
• Phone: +65 6908 2222
• Email: Srishti_CHHABRA[@]nuhs.edu.sg
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: January 27, 2027
• Est. primary completion date: April 23, 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Years and older

Eligibility

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 = 7 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

Related Conditions & MeSH terms

• Tuberculosis
• Tuberculosis, Pulmonary

Intervention

Drug:
• Doxycycline
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
Placebo + standard anti-tuberculous treatment

Locations

Country	Name	City	State
Singapore	National University Hospital	Singapore

Sponsors (4)

Lead Sponsor	Collaborator
National University Hospital, Singapore	Hospital Queen Elizabeth, Malaysia, National University of Singapore, Tan Tock Seng Hospital

Country where clinical trial is conducted

Singapore, 

References & Publications (1)

Miow QH, Vallejo AF, Wang Y, Hong JM, Bai C, Teo FS, Wang AD, Loh HR, Tan TZ, Ding Y, She HW, Gan SH, Paton NI, Lum J, Tay A, Chee CB, Tambyah PA, Polak ME, Wang YT, Singhal A, Elkington PT, Friedland JS, Ong CW. Doxycycline host-directed therapy in human pulmonary tuberculosis. J Clin Invest. 2021 Aug 2;131(15):e141895. doi: 10.1172/JCI141895. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Safety profile	Incidence of Grade 3 or 4 adverse events and serious adverse events	week 0 to 26
Secondary	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
Secondary	Cumulative lung cavity volume	Change in cumulative lung cavity volume (in cm3) measured on CT scan	week 0 to 26
Secondary	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
Secondary	Sputum TB culture	Time taken in days for positivity of sputum TB culture using MGIT will be assessed	up to 8 weeks
Secondary	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
Secondary	Sputum matrix metalloproteinase (MMP) concentration	Change of sputum matrix metalloproteinase (MMP) concentration will be measured by Luminex array	up to 8 weeks
Secondary	Sputum functional assays	Change in sputum functional assays by sputum collagenase and elastase assay will be assessed.	up to 8 weeks
Secondary	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
Secondary	Host plasma matrix metalloproteinase (MMP) concentration	Change in host plasma matrix metalloproteinase (MMP) concentration will be measured by Luminex array	week 0 to 26
Secondary	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

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