Azithromycin as Host-directed Therapy for Pulmonary Tuberculosis

NCT03160638 | Completed Phase 2

• 1 other identifier: AZT_DSTB_BB
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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

Conditions

Tuberculosis, Pulmonary

Keywords

Azithromycin; Immunomodulation; Pharmacokinetics; Tissue degradation; Tissue remodelling

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Pulmonary inflammation

  Before randomization and day 28

• Pulmonary inflammation

  Before randomization and day 28

• Pulmonary tissue degradation

  Before randomization and day 28

• Pulmonary tissue degradation

  Before randomization, day 7 and day 28

• Pulmonary tissue remodeling

  Before randomization and day 28

Other Outcomes (6)

• Evaluation of HRZE treatment outcomes

  Up to 6 months

• Evaluation of HRZE treatment outcomes

  Up to 6 months

• Drug exposure of azithromycin

  Day 7

Study Arms (2)

Azithromycin arm

EXPERIMENTAL

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

Drug: Azithromycin 250 mg

Standard of care arm

NO INTERVENTION

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

Interventions

Azithromycin 250 mg DRUG

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

Azithromycin arm

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Clinical diagnosis of drug sensitive pulmonary tuberculosis (molecular test; identification Mtb complex; absence of resistance genes such as rpob, inha, katg)
• Written informed consent

You may not qualify if:

• 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

Sponsors & Collaborators

• University Medical Center Groningen: lead

Study Sites (1)

University Medical Center Groningen

Groningen, 9700RB, Netherlands

Location

Related Publications (1)

• Dekkers BGJ, Kerstjens HAM, Breisnes HW, Leeming DJ, Anthony RM, Frijlink HW, van der Werf TS, Kosterink JGW, Alffenaar JC, Akkerman OW. Azithromycin as Host-Directed Therapy for Pulmonary Tuberculosis: A Randomized Pilot Trial. J Infect Dis. 2025 Jun 2;231(5):e891-e900. doi: 10.1093/infdis/jiaf069.

  PMID: 39932906 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

Azithromycin

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, PharmD, PhD

Model Details: Prospective, randomized pilot study

Study Record Dates

• First Submitted: May 11, 2017
• First Posted: May 19, 2017
• Study Start: February 1, 2018
• Primary Completion: May 22, 2022
• Study Completion: May 22, 2022
• Last Updated: February 26, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)