Doxycycline in Human Pulmonary Tuberculosis (Doxy-TB)

Doxycycline and the Modulation of Host Immunopathology in Human Pulmonary Tuberculosis: A Pilot Study

Pulmonary cavitation, a hallmark of tuberculosis (TB), is the site of high mycobacterial burden leading to disease transmission. The cause of tissue destruction leading to cavitation in TB is primarily due to the host inflammatory response. A matrix degrading phenotype develops in TB, in which the activity of host proteolytic enzymes, specifically matrix metalloproteinases (MMPs) is unopposed by their specific Tissue Inhibitors of Metalloproteinases (TIMPs), thus driving tissue destruction and cavitation in TB. This tissue destruction causes morbidity and mortality. MMP inhibition with doxycycline has shown to improve lung function in patients with chronic lung diseases but its use in TB is unclear.

We hypothesise that the MMP inhibitor doxycycline will reduce tissue destruction in human pulmonary tuberculosis.

Specific aims:

• To investigate the MMP and TIMP secretion and gene expression in M. tuberculosis (M.tb) - infected primary neutrophils and monocytes from healthy volunteers taking doxycycline.
• To investigate the intracellular signaling pathways modulated by doxycycline
• To investigate the effects doxycycline has on biological markers of tissue destruction in TB patients
• To assess the tolerability and side effects of doxycycline with concurrent standard TB therapy

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Drug: placebo; Drug: Doxycycline

Detailed Description

All TB patients are to keep to their standard anti-tuberculous treatment. A standardized questionnaire of symptoms, side-effects and weight shall be recorded. Induced sputum and plasma samples from all TB patients shall be analysed for MMPs and TIMPs before and after the administration of doxycycline for two weeks. In addition, neutrophils and mononuclear cells from TB patients and these shall be stimulated with live, virulent M. tuberculosis in a Biosafety Level 3 laboratory. The supernatants from these cells shall be analysed for MMPs and TIMPs.

Healthy volunteers shall be recruited and administered doxycycline for 2 weeks. Neutrophils and mononuclear cells will be isolated from blood prior to treatment, at weeks 2 and 8 and infected with M.tb. Cell culture supernatants and nucleic acids will be harvested. MMP and TIMP expression will be analysed using luminex array and real-time polymerase chain reaction. Intracellular signaling pathways will be examined with a human phospho-kinase array. Matrix destruction will be assessed using collagen quantitative fluorescent assays.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 119228
    • National University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Healthy Volunteers 10 volunteers will be recruited comprising 5 females and 5 males.

Inclusion criteria:

1. No known medical conditions
2. Aged 21 years to less than 70.

Exclusion criteria:

1. Unable to give informed consent
2. Prisoners
3. Pregnancy or nursing
4. On medication or oral contraceptives
5. Any concurrent illness, such as influenza

TB patients

Inclusion criteria: Patients should meet all criteria

1. Patients receiving ≤ 7 days of TB treatment or about to start standard combination TB treatment
2. Confirmed pulmonary TB with positive acid-fast bacilli smear and/or positive TB GeneXpert test and/or culture results
3. Chest radiograph demonstrating pulmonary involvement
4. Aged 21 years to less than 70

Exclusion criteria:

1. HIV co-infection
2. Previous pulmonary TB
3. Severe, pre-existing lung disease such as pulmonary fibrosis, bronchiectasis, Chronic obstructive pulmonary disease 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. Unable to provide informed consent
9. Haemoglobin < 8 g/dl
10. Creatinine 2 times upper limit of normal (ULN)
11. Alanine transaminase >3 times ULN
12. 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
13. Enrolment in any other clinical trial involving a systemic drug or intervention involving the lung
14. Evidence of severe depression, schizophrenia or mania
15. Principal investigator assessment of lack of willingness to participate and comply with all requirements of the protocol, or identification of any factor felt to significantly increase the participant's risk of suffering an adverse outcome

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Doxycycline; Doxycycline 100 mg twice daily with once daily anti-tuberculous treatment comprising of rifampicin 10 mg/kg, isoniazid 5 mg/kg, ethambutol 20 mg/kg, pyrazinamide 25 mg/kg and pyridoxine 10-50 mg per day according to managing physicians' discretion. These will be given daily for 14 days. 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
Placebo Comparator: Placebo; Placebo twice daily with once daily anti-tuberculous treatment comprising of rifampicin 10 mg/kg, isoniazid 5 mg/kg, ethambutol 20 mg/kg, pyrazinamide 25 mg/kg and pyridoxine 10-50 mg per day according to managing physicians' discretion. These will be given daily for 14 days. 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change of serum marker Procollagen III N-terminal peptide (PIIINP) from day 0 to day 14 in TB patients	Day 0 and Day 14

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of participants with treatment-related adverse events	day 0 to day 56

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Collaborators: Tan Tock Seng Hospital; National University, Singapore; A*Star

Publications and helpful links

General Publications

• 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). pii: 141895. doi: 10.1172/JCI141895.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): June 1, 2017
• Study Completion (Actual): June 1, 2017

Study Registration Dates

• First Submitted: March 11, 2016
• First Submitted That Met QC Criteria: May 12, 2016
• First Posted (Estimate): May 17, 2016

Study Record Updates

• Last Update Posted (Actual): November 27, 2017
• Last Update Submitted That Met QC Criteria: November 22, 2017
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Doxycycline
• Other Study ID Numbers: Doxy_TB