Clinical trial NCT03160638: Azithromycin as Host-directed Therapy for Pulmonary Tuberculosis
Official title: A Prospective, Randomized Pilot Study of the Immunomodulatory Effects of Azithromycin in Adults With Pulmonary Tuberculosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tuberculosis, Pulmonary
Keywords: Azithromycin
Immunomodulation
Pharmacokinetics
Tissue degradation
Tissue remodelling
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
First posted: 2017-05-19
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, randomized pilot study
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Systemic inflammation
timeFrame: Before randomization, day 7 and day 28
measure: Systemic inflammation
timeFrame: Before randomization, day 7 and day 28
Secondary outcomes:
measure: Pulmonary inflammation
timeFrame: Before randomization and day 28
measure: Pulmonary inflammation
timeFrame: Before randomization and day 28
measure: Pulmonary tissue degradation
timeFrame: Before randomization and day 28
measure: Pulmonary tissue degradation
timeFrame: Before randomization, day 7 and day 28
measure: Pulmonary tissue remodeling
timeFrame: Before randomization and day 28
measure: Pulmonary tissue remodeling
timeFrame: Before randomization, day 7 and day 28
Other outcomes:
measure: Evaluation of HRZE treatment outcomes
timeFrame: Up to 6 months
measure: Evaluation of HRZE treatment outcomes
timeFrame: Up to 6 months
measure: Drug exposure of azithromycin
timeFrame: Day 7
measure: Drug exposure of azithromycin
timeFrame: Day 7
measure: Drug exposure of azithromycin
timeFrame: Day 7
measure: Drug exposure of azithromycin
timeFrame: Day 7
Locations:
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
Study officials:
References: