Azithromycin as Host-directed Therapy for Pulmonary Tuberculosis

Study Overview
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Brief Summary
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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: To assess whether azithromycin enhances resolution of systemic inflammation in patients with drug susceptible pulmonary TB receiving standard treatment. 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 To investigate whether these effects are associated within shortening of the time to sputum conversion.

Official Title
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A Prospective, Randomized Pilot Study of the Immunomodulatory Effects of Azithromycin in Adults With Pulmonary Tuberculosis

Conditions
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Tuberculosis, Pulmonary

Intervention / Treatment
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* Drug: Azithromycin 250 mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomized pilot study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azithromycin arm<br>Patients in this arm will be treated with azithromycin 250 mg once daily on top of standard HRZE treatment. | Drug: Azithromycin 250 mg<br>* 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<br>|
| No Intervention: Standard of care arm<br>Patients in this arm will receive no additional treatment on top of standard HRZE treatment | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systemic inflammation | Changes in total & differential white blood cell counts markers | Before randomization, day 7 and day 28 | 
| Systemic inflammation | Changes in serum inflammatory markers | Before randomization, day 7 and day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary inflammation | Changes in total and differential sputum inflammatory cell counts | Before randomization and day 28 | 
| Pulmonary inflammation | Changes in cytokine levels in sputum | Before randomization and day 28 | 
| Pulmonary tissue degradation | Changes in markers of tissue degradation in sputum | Before randomization and day 28 | 
| Pulmonary tissue degradation | Changes in markers of tissue degradation in serum | Before randomization, day 7 and day 28 | 
| Pulmonary tissue remodeling | Changes in markers of tissue remodeling in sputum | Before randomization and day 28 | 
| Pulmonary tissue remodeling | Changes in markers of tissue remodeling in serum | Before randomization, day 7 and day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Azithromycin, Immunomodulation, Pharmacokinetics, Tissue degradation, Tissue remodelling