Azithromycin as Host-directed Therapy for Pulmonary Tuberculosis

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

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.

Study Overview

• Status: Completed
• Conditions: Tuberculosis, Pulmonary
• Intervention / Treatment: Drug: Azithromycin 250 mg

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Bart Dekkers, PharmD, PhD; Phone Number: +31506314070; Email: b.g.j.dekkers@umcg.nl
• Study Contact Backup: Name: Jan-Willem Alffenaar, PharmD, PhD; Phone Number: +31506314070; Email: j.w.c.alffenaar@umcg.nl

Study Locations

• Netherlands
  • Groningen, Netherlands, 9700RB
    • University Medical Center Groningen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 118 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2018
• Primary Completion (Actual): May 22, 2022
• Study Completion (Actual): May 22, 2022

Study Registration Dates

• First Submitted: May 11, 2017
• First Submitted That Met QC Criteria: May 18, 2017
• First Posted (Actual): May 19, 2017

Study Record Updates

• Last Update Posted (Estimated): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 23, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Azithromycin; Immunomodulation; Tissue degradation; Tissue remodelling
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: AZT_DSTB_BB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No