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Doxycycline in Human Pulmonary Tuberculosis (Doxy-TB)

Primary Purpose

Tuberculosis

Status
Completed
Phase
Phase 2
Locations
Singapore
Study Type
Interventional
Intervention
Doxycycline
placebo
Sponsored by
National University Hospital, Singapore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberculosis

Eligibility Criteria

21 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • National University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Doxycycline

Placebo

Arm Description

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 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

Outcomes

Primary Outcome Measures

Change of serum marker Procollagen III N-terminal peptide (PIIINP) from day 0 to day 14 in TB patients

Secondary Outcome Measures

Number of participants with treatment-related adverse events

Full Information

First Posted
March 11, 2016
Last Updated
November 22, 2017
Sponsor
National University Hospital, Singapore
Collaborators
Tan Tock Seng Hospital, National University of Singapore, A*Star
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1. Study Identification

Unique Protocol Identification Number
NCT02774993
Brief Title
Doxycycline in Human Pulmonary Tuberculosis
Acronym
Doxy-TB
Official Title
Doxycycline and the Modulation of Host Immunopathology in Human Pulmonary Tuberculosis: A Pilot Study
Study Type
Interventional

2. Study Status

Record Verification Date
May 2016
Overall Recruitment Status
Completed
Study Start Date
September 2015 (undefined)
Primary Completion Date
June 2017 (Actual)
Study Completion Date
June 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National University Hospital, Singapore
Collaborators
Tan Tock Seng Hospital, National University of Singapore, A*Star

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
40 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Doxycycline
Arm Type
Experimental
Arm Description
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
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Doxycycline
Intervention Type
Drug
Intervention Name(s)
placebo
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
Number of participants with treatment-related adverse events
Time Frame
day 0 to day 56

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Healthy Volunteers 10 volunteers will be recruited comprising 5 females and 5 males. Inclusion criteria: No known medical conditions Aged 21 years to less than 70. Exclusion criteria: Unable to give informed consent Prisoners Pregnancy or nursing On medication or oral contraceptives Any concurrent illness, such as influenza TB patients Inclusion criteria: Patients should meet all criteria 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 Exclusion criteria: 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 Patients on retinoic acid, neuromuscular blocking agents and pimozide which may increase risk of drug toxicity Autoimmune disease and/or on systemic immunosuppressants Unable to provide informed consent Haemoglobin < 8 g/dl Creatinine 2 times upper limit of normal (ULN) Alanine transaminase >3 times ULN 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 Enrolment in any other clinical trial involving a systemic drug or intervention involving the lung Evidence of severe depression, schizophrenia or mania 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
Facility Information:
Facility Name
National University Hospital
City
Singapore
ZIP/Postal Code
119228
Country
Singapore

12. IPD Sharing Statement

Citations:
PubMed Identifier
34128838
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.
Results Reference
derived

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Doxycycline in Human Pulmonary Tuberculosis

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