1. To assess whether azithromycin enhances resolution of systemic inflammation in patients with drug susceptible pulmonary TB receiving HRZE treatment. 2. To assess whether azithromycin on top of HRZE treatment in patients with drug susceptible…
ID
Source
Brief title
Condition
- Mycobacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective will be studied by measuring total white blood cell
count, blood cell differential counts and serum inflammatory markers.
Secondary outcome
The secondary objective will be studied by measuring inflammatory cell counts,
differential cell counts, cytokines and markers of tissue degradation and
remodeling in induced sputum.
Background summary
Tuberculosis (TB) presents one of the most deadly communicable diseases in the
world, causing an estimated 10.4 million new cases and 1.8 million TB deaths in
2015. Currently, treatment is focused on eradication of the bacterial
infection, however, after treatment approximately half of patients are left
with a significant and permanent respiratory impairment. This impairment is
thought to be due to tissue damage due to sustained inflammation resulting in a
chronic obstructive pulmonary disease (COPD)-like phenotype. In addition to
these chronic effects, acute paradoxical reactions, characterized by increased
inflammatory symptoms have also been described in TB patients shortly after
initiating antimicrobial treatment.
Immune cells control infection by activating both pro- and anti-inflammatory
processes. These immune cells may, however, also contribute to tissue
destruction, airway remodeling and progressive disease manifestations in TB,
resulting in severe sequelae. Adjunctive host-directed therapies are being
investigated in order to modulate host immune responses to target Mtb infection
and/or reduce excessive inflammation, prevent pathological tissue damage,
preserve lung function and enhance effectiveness of standard drug therapy,
while nonetheless eliminating M. tuberculosis bacilli. 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.
The immunomodulatory effects of azithromycin in TB are currently unknown.
Therefore, the current project aims to investigate the effects of azithromycin
on immune responses in patients with drug susceptible pulmonary TB. We
hypothesize that azithromycin will reduce pro-inflammatory and increase
anti-inflammatory cytokine levels and reduce associated inflammation in
patients with TB. This reduction in inflammation is expected to be associated
with a reduction in expression of markers of tissue damage and increased
expression of markers for tissue repair.
Study objective
1. To assess whether azithromycin enhances resolution of systemic inflammation
in patients with drug susceptible pulmonary TB receiving HRZE treatment.
2. To assess whether azithromycin on top of HRZE 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 with drug exposure of
anti-TB drugs and azithromycin.
Study design
A prospective, randomized open label intervention trial to investigate the
immunomodulatory effects of azithromycin
Intervention
Included patients will be treated with azithromycin 250 mg once daily or
standard of care (no additional treatment) for 28 days. An azithromycin
loading dose of 500 mg (two tablets of 250 mg) will be administered on day 1
Study burden and risks
There are no direct benefits for the patients to be included. The risk
associated with the use of azithromycin is low as the dose of azithromycin is
low. Mild side effects may occur, as azithromycin is a generally well-tolerated
drug. The patients could have mild discomfort as a consequent of venous blood
sampling and sputum collection.
Hanzeplein 1
Groningen 9713 GV
NL
Hanzeplein 1
Groningen 9713 GV
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all of the following criteria:
- Microbiological proven diagnosis of drug sensitive pulmonary tuberculosis (by culture and/or molecular test.; 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). See attachment A for a full list of these drugs.
- Treatment with digoxin
- Patients with gastrointestinal complaints, like diarrhea and vomiting (>=grade 2, observed; diarrhea: increase of 4-6 stools per day over baseline; vomiting: >=3-5 episodes (separated by 5 minutes) in 24 hours)
- 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, for calculation of the score, see attachment B)
- Patients with a known QTc >=500 ms. An electrocardiogram (ECG) will be recorded.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-001929-40-NL |
| ClinicalTrials.gov | NCT03160638 |
| CCMO | NL61966.042.17 |