Clinical trial NCT05473520: Doxycycline Host-directed Therapy to Improve Lung Function and Decrease Tissue Destruction in Pulmonary Tuberculosis
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Tuberculosis
Lead sponsor: National University Hospital, Singapore
Sponsor class: OTHER
Collaborators: name: Tan Tock Seng Hospital
name: Hospital Queen Elizabeth, Malaysia
name: National University of Singapore
name: University Malaysia Sabah
name: Menggatal Health Clinic, Sabah, Malaysia
name: Luyang Health Clinic, Sabah, Malaysia
First posted: 2022-07-26
Enrollment: 150
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Forced expiratory volume in 1 second (FEV1) at 26 weeks measured by spirometry
timeFrame: week 0 to 26
Secondary outcomes:
measure: Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC ratio)
timeFrame: at 26 weeks
measure: Safety profile
timeFrame: week 0 to 26
measure: Resolution of pulmonary cavities on CT scan
timeFrame: at 26 weeks
measure: Cumulative lung cavity volume
timeFrame: week 0 to 26
measure: St George's Respiratory Questionnaire Score
timeFrame: week 0 to 26
measure: Sputum TB culture
timeFrame: up to 8 weeks
measure: Sputum culture conversion
timeFrame: up to 8 weeks
measure: Sputum matrix metalloproteinase (MMP) concentration
timeFrame: up to 8 weeks
measure: Sputum functional assays
timeFrame: up to 8 weeks
measure: Host transcriptome
timeFrame: week 0 to 26
measure: Host plasma matrix metalloproteinase (MMP) concentration
timeFrame: week 0 to 26
measure: Pharmacokinetics and pharmacodynamics of drug concentrations
timeFrame: week 2
Other outcomes:
Locations:
city: Kota Kinabalu
country: Malaysia
facility: Hospital Queen Elizabeth I
state: Sabah
city: Kota Kinabalu
country: Malaysia
facility: Universiti Malaysia Sabah (UMS), Borneo Medical and Health Research Centre
state: Sabah
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: TB Control Unit
Study officials:
affiliation: National University Hospital, Singapore
name: Catherine Ong, MRCP PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.