Doxycycline in Human Pulmonary Tuberculosis

NCT02774993 | Completed Phase 2 DMC

• 1 other identifier: Doxy_TB
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Tuberculosis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Number of participants with treatment-related adverse events

  day 0 to day 56

Study Arms (2)

Doxycycline

EXPERIMENTAL

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

PLACEBO COMPARATOR

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

Interventions

Doxycycline DRUG

Doxycycline

placebo DRUG

Placebo

Eligibility Criteria

• Age: 21 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• Unable to give informed consent
• Prisoners
• Pregnancy or nursing
• On medication or oral contraceptives
• Any concurrent illness, such as influenza
• TB patients
• Patients receiving ≤ 7 days of TB treatment or about to start standard combination TB treatment
• Confirmed pulmonary TB with positive acid-fast bacilli smear and/or positive TB GeneXpert test and/or culture results
• Chest radiograph demonstrating pulmonary involvement
• Aged 21 years to less than 70
• HIV co-infection
• Previous pulmonary TB
• Severe, pre-existing lung disease such as pulmonary fibrosis, bronchiectasis, Chronic obstructive pulmonary disease and lung cancer
• Pregnant or breast feeding
• Allergies to tetracyclines

Sponsors & Collaborators

• National University Hospital, Singapore: lead
• Tan Tock Seng Hospital: collaborator
• National University of Singapore: collaborator
• A*Star: collaborator

Study Sites (1)

National University Hospital

Singapore, 119228, Singapore

Location

Related 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.

  PMID: 34128838 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

Doxycycline

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 11, 2016
• First Posted: May 17, 2016
• Study Start: September 1, 2015
• Primary Completion: June 1, 2017
• Study Completion: June 1, 2017
• Last Updated: November 27, 2017

Record last verified: 2016-05

Locations

SG (1)