Tuberculosis, Pulmonary
Conditions
Keywords
Azithromycin, Immunomodulation, Pharmacokinetics, Tissue degradation, Tissue remodelling
Brief summary
Rationale: Treatment in tuberculosis (TB) is focused on eradication of the bacterial infection, however, after treatment approximately half of patients are left with a significant and permanent respiratory impairment. Adjunctive host-directed therapies are being investigated to modulate host immune responses to target mycobacterium tuberculosis (Mtb) infection and/or reduce excessive inflammation, prevent pathological tissue damage, preserve lung function and enhance effectiveness of standard drug therapy, while nonetheless eliminating Mtb. Macrolide antibiotics have previously been used in the treatment of multidrug-resistant TB. In addition to their antibiotic effects, macrolides have also been recognized to induce anti-inflammatory and immunomodulatory effects in other lung diseases. Objective: To investigate the immunomodulatory effects of azithromycin in tuberculosis patients receiving standard therapy (isoniazid, rifampicin, pyrazinamide, ethambutol (HRZE)) Study design: A prospective, randomized open label intervention trial to investigate the immunomodulatory effects of azithromycin Study population: 24 Intervention: azithromycin 250 mg once daily or standard of care (control) Main study parameters/endpoints: 1. To assess whether azithromycin enhances resolution of systemic inflammation in patients with drug susceptible pulmonary TB receiving standard treatment. 2. To assess whether azithromycin on top of standard treatment in patients with drug susceptible pulmonary TB reduces airway inflammation and reduces tissue degradation and remodeling 3. To investigate whether these effects are associated within shortening of the time to sputum conversion.
Interventions
Patients will be treated with azithromycin 250 mg once daily for 28 days. An azithromycin loading dose of 500 mg (two tablets of 250 mg) will be administered on day 1
Sponsors
University Medical Center Groningen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective, randomized pilot study
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of drug sensitive pulmonary tuberculosis (molecular test; identification Mtb complex; absence of resistance genes such as rpob, inha, katg) * Written informed consent
Exclusion criteria
* Patient reported previous history of treatment for tuberculosis * Patients younger than 18 years * Pregnancy or breast feeding * Patients with hypersensitivity to macrolide antibiotics * Treatment with any macrolide in the previous month * Treatment with any tetracycline in the previous month * Treatment with any inhaled or oral corticosteroid in the previous month * Concomitant treatment with analgesic (NSAIDs)/immunosuppressant drugs (except paracetamol). * Treatment with digoxin * Patients with gastrointestinal complaints, like diarrhea and vomiting (≥grade 2, observed) * Other known respiratory diseases, including bronchiectasis, pulmonary fibrosis, pulmonary vascular disease or lung cancer * HIV-1 infection or AIDS * Impaired liver function (Child-Pugh score C) * Patients with a known QTc ≥500 ms. An electrocardiogram (ECG) will be recorded. * Inability to spontaneously produce sputum upon diagnosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Systemic inflammation | Before randomization, day 7 and day 28 | Changes in total & differential white blood cell counts markers |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pulmonary inflammation | Before randomization and day 28 | Changes in total and differential sputum inflammatory cell counts |
| Pulmonary tissue degradation | Before randomization and day 28 | Changes in markers of tissue degradation in sputum |
| Pulmonary tissue remodeling | Before randomization and day 28 | Changes in markers of tissue remodeling in sputum |
Other
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of HRZE treatment outcomes | Up to 6 months | Time to sputum conversion |
| Drug exposure of azithromycin | Day 7 | AUC0-24h of azithromycin in TB |
Countries
Netherlands
Outcome results
None listed