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

NCT ID: NCT05473520

Last Updated: 2025-09-09

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 150 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-05-24
• Study Completion Date: 2030-01-31

Brief Summary

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.

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 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.

Conditions

Tuberculosis; Acute Coronary Syndrome; Pulmonary Hypertension (Diagnosis)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Doxycycline + standard anti-tuberculous treatment

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

Group Type: EXPERIMENTAL

Doxycycline

Intervention Type: DRUG

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 + standard anti-tuberculous treatment

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo + standard anti-tuberculous treatment

Interventions

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.

Intervention Type: DRUG

Placebo

Placebo + standard anti-tuberculous treatment

Intervention Type: DRUG

Eligibility Criteria

Inclusion 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

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tan Tock Seng Hospital

OTHER

Sponsor Role: collaborator

Hospital Queen Elizabeth, Malaysia

OTHER_GOV

Sponsor Role: collaborator

National University of Singapore

OTHER

Sponsor Role: collaborator

University Malaysia Sabah

UNKNOWN

Sponsor Role: collaborator

Menggatal Health Clinic, Sabah, Malaysia

UNKNOWN

Sponsor Role: collaborator

Luyang Health Clinic, Sabah, Malaysia

UNKNOWN

Sponsor Role: collaborator

National University Hospital, Singapore

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Catherine Ong, MRCP PhD

Role: PRINCIPAL_INVESTIGATOR

National University Hospital, Singapore

Locations

Hospital Queen Elizabeth I

Kota Kinabalu, Sabah, Malaysia

Site Status: NOT_YET_RECRUITING

Klinik Kesihatan Luyang

Kota Kinabalu, Sabah, Malaysia

Site Status: ACTIVE_NOT_RECRUITING

Klinik Kesihatan Menggatal

Kota Kinabalu, Sabah, Malaysia

Site Status: RECRUITING

Universiti Malaysia Sabah (UMS), Borneo Medical and Health Research Centre

Kota Kinabalu, Sabah, Malaysia

Site Status: ACTIVE_NOT_RECRUITING

National University Hospital

Singapore, , Singapore

Site Status: RECRUITING

TB Control Unit

Singapore, , Singapore

Site Status: RECRUITING

Countries

Malaysia; Singapore

Central Contacts

Srishti CHHABRA, MBBS BSc MRCP

Role: CONTACT

srishti.chhabra@mohh.com.sg

+65 6908 2222

Facility Contacts

Nurul Ain Mohd Yaakub, Dr

Role: primary

nurulainykb@moh.gov.my

Dr Siti Nor Aishah bt Abdul Rahim

Role: primary

+60192462367

Dr. Saravanan A/L Jayaraman

Role: backup

+60168040532

Catherine ONG, MRCP PhD

Role: primary

catherine_wm_ong@nuhs.edu.sg <catherine_wm_ong@nuhs.edu.sg>

Shera Tan, Dr

Role: primary

shera_tan@ttsh.com.sg

+65 6511 5131

References

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.

Reference Type: BACKGROUND

PMID: 34128838 (View on PubMed)

Related Links

https://pubmed.ncbi.nlm.nih.gov/34128838/

Publication

Other Identifiers

Phase III Doxy-TB

Identifier Type: -

Identifier Source: org_study_id