Azithromycin as Host-directed Therapy for Pulmonary Tuberculosis

Sponsor

University Medical Center Groningen (Other)

Overall Status

Recruiting

CT.gov ID

NCT03160638

Collaborator

(none)

Enrollment

Location

Arms

62.9

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

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:

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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis, Pulmonary	Drug: Azithromycin 250 mg	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

24 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Prospective, randomized pilot studyProspective, randomized pilot study

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Feb 1, 2018

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Apr 30, 2023

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Azithromycin arm

Patients in this arm will be treated with azithromycin 250 mg once daily on top of standard HRZE treatment.

Drug: Azithromycin 250 mg

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

No Intervention: Standard of care arm

Patients in this arm will receive no additional treatment on top of standard HRZE treatment

Outcome Measures

Primary Outcome Measures

Systemic inflammation [Before randomization, day 7 and day 28]
Changes in total & differential white blood cell counts markers
Systemic inflammation [Before randomization, day 7 and day 28]
Changes in serum inflammatory markers

Secondary Outcome Measures

Pulmonary inflammation [Before randomization and day 28]
Changes in total and differential sputum inflammatory cell counts
Pulmonary inflammation [Before randomization and day 28]
Changes in cytokine levels in sputum
Pulmonary tissue degradation [Before randomization and day 28]
Changes in markers of tissue degradation in sputum
Pulmonary tissue degradation [Before randomization, day 7 and day 28]
Changes in markers of tissue degradation in serum
Pulmonary tissue remodeling [Before randomization and day 28]
Changes in markers of tissue remodeling in sputum
Pulmonary tissue remodeling [Before randomization, day 7 and day 28]
Changes in markers of tissue remodeling in serum

Other Outcome Measures

Evaluation of HRZE treatment outcomes [Up to 6 months]
Time to sputum conversion
Evaluation of HRZE treatment outcomes [Up to 6 months]
Drug exposure of HRZE in relation to minimal inhibitory concentration (MIC) of Mtb for HRZE
Drug exposure of azithromycin [Day 7]
AUC0-24h of azithromycin in TB
Drug exposure of azithromycin [Day 7]
Metabolic clearance (CLm) of azithromycin in TB
Drug exposure of azithromycin [Day 7]
Volume of distribution (V) of azithromycin in TB
Drug exposure of azithromycin [Day 7]
Elimination half-life (T1/2) of azithromycin in TB

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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