Doxycycline in Human Pulmonary Tuberculosis (Doxy-TB)
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|ClinicalTrials.gov Identifier: NCT02774993|
Recruitment Status : Completed
First Posted : May 17, 2016
Last Update Posted : November 27, 2017
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.
- 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
|Condition or disease||Intervention/treatment||Phase|
|Tuberculosis||Drug: Doxycycline Drug: placebo||Phase 2|
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 (Clinical Trial)|
|Actual Enrollment :||40 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Official Title:||Doxycycline and the Modulation of Host Immunopathology in Human Pulmonary Tuberculosis: A Pilot Study|
|Study Start Date :||September 2015|
|Actual Primary Completion Date :||June 2017|
|Actual Study Completion Date :||June 2017|
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
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
- Change of serum marker Procollagen III N-terminal peptide (PIIINP) from day 0 to day 14 in TB patients [ Time Frame: Day 0 and Day 14 ]
- Number of participants with treatment-related adverse events [ Time Frame: day 0 to day 56 ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02774993
|National University Hospital|
|Singapore, Singapore, 119228|