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Azithromycin as Host-directed Therapy for Pulmonary Tuberculosis

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ClinicalTrials.gov Identifier: NCT03160638
Recruitment Status : Recruiting
First Posted : May 19, 2017
Last Update Posted : October 10, 2019
Sponsor:
Information provided by (Responsible Party):
Jan-Willem C Alffenaar, University Medical Center Groningen

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.

Condition or disease Intervention/treatment Phase
Tuberculosis, Pulmonary Drug: Azithromycin 250 mg Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Prospective, 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 : February 1, 2018
Estimated Primary Completion Date : February 1, 2020
Estimated Study Completion Date : April 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

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



Primary Outcome Measures :
  1. Systemic inflammation [ Time Frame: Before randomization, day 7 and day 28 ]
    Changes in total & differential white blood cell counts markers

  2. Systemic inflammation [ Time Frame: Before randomization, day 7 and day 28 ]
    Changes in serum inflammatory markers


Secondary Outcome Measures :
  1. Pulmonary inflammation [ Time Frame: Before randomization and day 28 ]
    Changes in total and differential sputum inflammatory cell counts

  2. Pulmonary inflammation [ Time Frame: Before randomization and day 28 ]
    Changes in cytokine levels in sputum

  3. Pulmonary tissue degradation [ Time Frame: Before randomization and day 28 ]
    Changes in markers of tissue degradation in sputum

  4. Pulmonary tissue degradation [ Time Frame: Before randomization, day 7 and day 28 ]
    Changes in markers of tissue degradation in serum

  5. Pulmonary tissue remodeling [ Time Frame: Before randomization and day 28 ]
    Changes in markers of tissue remodeling in sputum

  6. Pulmonary tissue remodeling [ Time Frame: Before randomization, day 7 and day 28 ]
    Changes in markers of tissue remodeling in serum


Other Outcome Measures:
  1. Evaluation of HRZE treatment outcomes [ Time Frame: Up to 6 months ]
    Time to sputum conversion

  2. Evaluation of HRZE treatment outcomes [ Time Frame: Up to 6 months ]
    Drug exposure of HRZE in relation to minimal inhibitory concentration (MIC) of Mtb for HRZE

  3. Drug exposure of azithromycin [ Time Frame: Day 7 ]
    AUC0-24h of azithromycin in TB

  4. Drug exposure of azithromycin [ Time Frame: Day 7 ]
    Metabolic clearance (CLm) of azithromycin in TB

  5. Drug exposure of azithromycin [ Time Frame: Day 7 ]
    Volume of distribution (V) of azithromycin in TB

  6. Drug exposure of azithromycin [ Time Frame: Day 7 ]
    Elimination half-life (T1/2) of azithromycin in TB



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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03160638


Contacts
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Contact: Bart Dekkers, PharmD, PhD +31506314070 b.g.j.dekkers@umcg.nl
Contact: Jan-Willem Alffenaar, PharmD, PhD +31506314070 j.w.c.alffenaar@umcg.nl

Locations
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Netherlands
University Medical Center Groningen Recruiting
Groningen, Netherlands, 9700RB
Contact: Bart GJ Dekkers, PharmD, PhD    +315014071    b.g.j.dekkers@umcg.nl   
Contact: Jan-Willem C Alffenaar, PharmD, PhD    +315014071    j.w.c.alffenaar@umcg.nl   
Sponsors and Collaborators
University Medical Center Groningen

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Responsible Party: Jan-Willem C Alffenaar, Principal Investigator, PharmD, PhD, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT03160638     History of Changes
Other Study ID Numbers: AZT_DSTB_BB
First Posted: May 19, 2017    Key Record Dates
Last Update Posted: October 10, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Jan-Willem C Alffenaar, University Medical Center Groningen:
Azithromycin
Immunomodulation
Pharmacokinetics
Tissue degradation
Tissue remodelling
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Azithromycin
Anti-Bacterial Agents
Anti-Infective Agents