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

Primary Purpose

Tuberculosis

Status
Not yet recruiting
Phase
Phase 3
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 - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

The recruitment target would be 150 patients, with 75 in each arm

Inclusion criteria: Patients should meet all 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

Sites / Locations

  • National University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Doxycycline + standard anti-tuberculous treatment

Placebo + standard anti-tuberculous treatment

Arm Description

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

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.

Outcomes

Primary Outcome Measures

Forced expiratory volume in 1 second (FEV1) at 26 weeks measured by spirometry
- FEV1 at 26 weeks, expressed as a percentage predicted for age, sex, height and race will be measured by spirometry and will be compared between the doxycycline and placebo group

Secondary Outcome Measures

Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC ratio)
Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC ratio) measured by spirometry
Safety profile
Incidence of Grade 3 or 4 adverse events and serious adverse events
Resolution of pulmonary cavities on CT scan
Proportion of patients in each study group with resolution of pulmonary cavities on CT scan done at 26 weeks
Cumulative lung cavity volume
Change in cumulative lung cavity volume (in cm3) measured on CT scan
St George's Respiratory Questionnaire Score
Change in Quality-of-life score by the St George's Respiratory Questionnaire will be measured. Scores range from 0 to 100, with higher scores indicating more limitations.
Sputum TB culture
Time taken in days for positivity of sputum TB culture using MGIT will be assessed
Sputum culture conversion
Time taken for sputum culture conversion (time taken for sputum cultures to turn negative) by liquid and solid cultures will be investigated
Sputum matrix metalloproteinase (MMP) concentration
Change of sputum matrix metalloproteinase (MMP) concentration will be measured by Luminex array
Sputum functional assays
Change in sputum functional assays by sputum collagenase and elastase assay will be assessed.
Host transcriptome
Change of host transcriptome will be measured via bulk RNA sequencing. In addition, in the subset of patients recruited from Singapore, single-cell RNA sequencing (scRNAseq) will be performed for neutrophils and peripheral blood mononuclear cells on 10 patients each from the doxycycline and placebo arm, analysing 10,000 cells per sample.
Host plasma matrix metalloproteinase (MMP) concentration
Change in host plasma matrix metalloproteinase (MMP) concentration will be measured by Luminex array
Pharmacokinetics and pharmacodynamics of drug concentrations
Sputum and plasma drug concentration of rifampicin, isoniazid, ethambutol, pyrazinamide (if prescribed) and doxycycline for a subset PK/PD study

Full Information

First Posted
June 13, 2022
Last Updated
September 25, 2023
Sponsor
National University Hospital, Singapore
Collaborators
Tan Tock Seng Hospital, Hospital Queen Elizabeth, Malaysia, National University of Singapore
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1. Study Identification

Unique Protocol Identification Number
NCT05473520
Brief Title
Doxycycline Host-directed Therapy to Improve Lung Function and Decrease Tissue Destruction in Pulmonary Tuberculosis
Acronym
Doxy-TB
Official Title
Doxycycline Host-directed Therapy to Improve Lung Function and Decrease Tissue Destruction in Pulmonary Tuberculosis: A Phase III Randomized Control Trial (Doxy-TB)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
October 24, 2023 (Anticipated)
Primary Completion Date
April 23, 2026 (Anticipated)
Study Completion Date
January 27, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National University Hospital, Singapore
Collaborators
Tan Tock Seng Hospital, Hospital Queen Elizabeth, Malaysia, National University of Singapore

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Tuberculosis (TB) is a global pandemic that despite successful treatment and bacterial eradication can cause chronic ill health, also known as pulmonary impairment after tuberculosis (PIAT). A recent Phase 2b double-blind randomised-controlled clinical trial shows that adjunctive doxycycline therapy along with standard pulmonary TB (PTB) treatment is safe, accelerates resolution of inflammation, suppresses tissue damaging enzyme activity and decreases pulmonary cavity volume (1). The investigators aim to determine if adjunctive doxycycline can reduce PIAT in a fully powered Phase III trial of 8 weeks of adjunctive doxycycline alongside standard pulmonary TB treatment. The investigators hypothesize that doxycycline inhibits tissue destruction in patients with pulmonary tuberculosis (PTB) and thereby leads to improved lung function after treatment. Specific aims To assess for improvement in lung function as measured by forced expiratory volume (FEV1) predicted in PTB patients given doxycycline versus placebo. To investigate whether doxycycline will hasten the resolution of pulmonary cavities measured by CT thorax, suppress inflammatory markers including matrix metalloproteinases and accelerate time to sputum culture conversion. 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 four 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 and non-contrast CT thorax 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. Accomplishing these specific aims will determine if doxycycline decreases PIAT by improving lung function, reducing pulmonary cavities and accelerating sputum culture conversion. 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.

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 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Doxycycline + standard anti-tuberculous treatment
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 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
Arm Title
Placebo + standard anti-tuberculous treatment
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 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.
Intervention Type
Drug
Intervention Name(s)
Doxycycline
Intervention Description
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
Intervention Name(s)
Placebo
Intervention Description
Placebo + standard anti-tuberculous treatment
Primary Outcome Measure Information:
Title
Forced expiratory volume in 1 second (FEV1) at 26 weeks measured by spirometry
Description
- FEV1 at 26 weeks, expressed as a percentage predicted for age, sex, height and race will be measured by spirometry and will be compared between the doxycycline and placebo group
Time Frame
week 0 to 26
Secondary Outcome Measure Information:
Title
Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC ratio)
Description
Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC ratio) measured by spirometry
Time Frame
at 26 weeks
Title
Safety profile
Description
Incidence of Grade 3 or 4 adverse events and serious adverse events
Time Frame
week 0 to 26
Title
Resolution of pulmonary cavities on CT scan
Description
Proportion of patients in each study group with resolution of pulmonary cavities on CT scan done at 26 weeks
Time Frame
at 26 weeks
Title
Cumulative lung cavity volume
Description
Change in cumulative lung cavity volume (in cm3) measured on CT scan
Time Frame
week 0 to 26
Title
St George's Respiratory Questionnaire Score
Description
Change in Quality-of-life score by the St George's Respiratory Questionnaire will be measured. Scores range from 0 to 100, with higher scores indicating more limitations.
Time Frame
week 0 to 26
Title
Sputum TB culture
Description
Time taken in days for positivity of sputum TB culture using MGIT will be assessed
Time Frame
up to 8 weeks
Title
Sputum culture conversion
Description
Time taken for sputum culture conversion (time taken for sputum cultures to turn negative) by liquid and solid cultures will be investigated
Time Frame
up to 8 weeks
Title
Sputum matrix metalloproteinase (MMP) concentration
Description
Change of sputum matrix metalloproteinase (MMP) concentration will be measured by Luminex array
Time Frame
up to 8 weeks
Title
Sputum functional assays
Description
Change in sputum functional assays by sputum collagenase and elastase assay will be assessed.
Time Frame
up to 8 weeks
Title
Host transcriptome
Description
Change of host transcriptome will be measured via bulk RNA sequencing. In addition, in the subset of patients recruited from Singapore, single-cell RNA sequencing (scRNAseq) will be performed for neutrophils and peripheral blood mononuclear cells on 10 patients each from the doxycycline and placebo arm, analysing 10,000 cells per sample.
Time Frame
week 0 to 26
Title
Host plasma matrix metalloproteinase (MMP) concentration
Description
Change in host plasma matrix metalloproteinase (MMP) concentration will be measured by Luminex array
Time Frame
week 0 to 26
Title
Pharmacokinetics and pharmacodynamics of drug concentrations
Description
Sputum and plasma drug concentration of rifampicin, isoniazid, ethambutol, pyrazinamide (if prescribed) and doxycycline for a subset PK/PD study
Time Frame
week 2

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
The recruitment target would be 150 patients, with 75 in each arm Inclusion criteria: Patients should meet all criteria: Aged 21 years and above 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 nucleic acid amplification test (NAAT) and/or TB culture results CXR demonstrating pulmonary involvement with cavity or cavities Able to provide informed consent Exclusion criteria: HIV co-infection Previous pulmonary TB Severe, pre-existing lung disease such as pulmonary fibrosis, bronchiectasis, COPD 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 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 ALT > 3 times upper limit of normal Creatinine > 2 times upper limit of normal 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Srishti CHHABRA, MBBS
Phone
+65 6908 2222
Email
Srishti_CHHABRA@nuhs.edu.sg
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Catherine Ong, MRCP PhD
Organizational Affiliation
National University Hospital, Singapore
Official's Role
Principal Investigator
Facility Information:
Facility Name
National University Hospital
City
Singapore
ZIP/Postal Code
119228
Country
Singapore
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Catherine ONG, MRCP PhD
Email
catherine_wm_ong@nuhs.edu.sg <catherine_wm_ong@nuhs.edu.sg>

12. IPD Sharing Statement

Plan to Share IPD
No
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
background
Links:
URL
https://pubmed.ncbi.nlm.nih.gov/34128838/
Description
Publication

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

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