A Pilot Study of Azithromycin Prophylaxis for Acute Chest Syndrome in Sickle Cell Disease

June 19, 2018 updated by: Suvankar Majumdar, University of Mississippi Medical Center
Acute chest syndrome (ACS), a lung complication in sickle cell disease (SCD), is the second most common cause of hospitalization and leading cause of death in SCD. ACS is associated with airway inflammation, and a major cause is pulmonary infection from atypical organisms. To date, there are no drugs available to reduce inflammation and risk of recurrent ACS. Macrolides are a group of antibiotics that exert immunomodulatory and anti-inflammatory actions both in vitro and in vivo. In addition, macrolides reduce bacterial burden in the airway of atypical organisms, all of which play an important role in the pathophysiology of ACS. Numerous studies have evaluated macrolide prophylaxis in conditions associated with lung inflammation, such as cystic fibrosis, asthma, bronchiectasis etc., and high quality evidence have found macrolides to be beneficial as a disease modifying agent that leads to improvement in airway inflammation, reduced pulmonary exacerbations and improved lung function. The investigators hypothesize that azithromycin prophylaxis is well tolerated and has the potential to reduce inflammation and improve lung outcome in children with SCD with a history of ACS. A prospective, single arm, open label feasibility study of azithromycin prophylaxis will be performed in children with SCD with a history ACS with the specific aim to examine the feasibility, safety and tolerability of azithromycin prophylaxis administration in participants with SCD , and to examine whether azithromycin prophylaxis has the potential to improve lung outcome. In addition, this study will determine whether azithromycin prophylaxis reduces inflammation in participants with SCD with a history of ACS.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Specific Aims:

Acute chest syndrome (ACS), a lung complication in sickle cell disease (SCD), is the second most common cause of hospitalization and leading cause of death in SCD. Recurrent ACS has been associated with poor lung function outcome that is comparable to cystic fibrosis. ACS is associated with airway inflammation, and a major cause is pulmonary infection from atypical organisms. To date, there are no drugs available to reduce inflammation and risk of recurrent ACS. Thus newer therapies are urgently needed to address this important issue associated with increased morbidity from debilitating chronic lung disease and mortality in SCD. Macrolides are a group of antibiotics that exert immunomodulatory and anti-inflammatory actions both in vitro and in vivo. It has been shown to inhibit neutrophil activation and mobilization, modulate oxidant production by neutrophils and of proinflammatory cytokine synthesis and release by leukocytes, reduce systemic markers of inflammation, inhibit intercellular adhesion molecules on epithelial cell surfaces, and block the activation of certain nuclear transcription factors. In addition, macrolides reduce bacterial burden in the airway of atypical organisms, all of which play an important role in the pathophysiology of ACS. Indeed, numerous studies have evaluated macrolide prophylaxis in conditions associated with lung inflammation, such as cystic fibrosis, asthma, bronchiectasis etc., and high quality evidence have found macrolides to be beneficial as a disease modifying agent that leads to improvement in airway inflammation, reduced pulmonary exacerbations and improved lung function. However, azithromycin has never been studied before in SCD. The investigators hypothesize that azithromycin prophylaxis is well tolerated and has the potential to reduce inflammation and improve lung outcome in children with SCD with a history of ACS.

A prospective, single arm, open label feasibility study of azithromycin prophylaxis will be performed in children with SCD with a history ACS with the following specific aims:

Specific Aim 1: Examine the feasibility, safety and tolerability of azithromycin prophylaxis administration in children with SCD. A cohort of 15 participants with sickle cell disease 6 to 16 years old will be placed on azithromycin prophylaxis, and followed closely to evaluate medication adherence and for any adverse effects from taking the medication.

Specific Aim 2: Examine whether azithromycin prophylaxis has the potential to improve lung outcome in participants with SCD with a history of ACS. In the same cohort of 15 patients, baseline pulmonary function testing will be performed evaluating Forced expiratory volume 1 sec (FEV1) and Forced vital capacity (FVC) measurements prior to starting azithromycin prophylaxis, and then again at study end period after 1 year to evaluate for any change.

Specific Aim 3: Determine whether azithromycin prophylaxis reduces inflammation in participants with SCD with a history of ACS. In the same cohort of 15 participants, baseline markers of inflammation will be performed, specifically C-reactive protein (CRP), Tumor necrosis factor Alpha (TNF-α), interleukin IL-1, IL-1β, IL-4, IL-6, and IL-8, and then repeated at specific time intervals of 16 weeks, 32 weeks and 48 weeks (study end).

Study Type

Interventional

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Mississippi
      • Jackson, Mississippi, United States, 39216
        • University of Mississippi Medical Center
    • Tennessee
      • Nashville, Tennessee, United States
        • Vanderbilt University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

4 years to 14 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Established diagnosis of SCD (Hemoglobin SS, hemoglobin Sβ0 thalassemia)
  • History of acute chest syndrome - the history of acute chest syndrome will be confirmed by a retrospective medical chart review that meets the standard definition as mentioned in the Background section.
  • Age ≥ 6 years to 16 years old

Exclusion Criteria:

  • Hemoglobin Sβ+thalassemia and hemoglobin SC subject will be excluded as this group of patients do not typically have severe SCD that places them at risk of developing recurrent acute chest syndrome
  • No history of acute chest syndrome
  • Significant neurologic impairment as judged by health care provider.
  • Inability to take/swallow a tablet
  • History of poor adherence to clinic visits.
  • History of renal or hepatic dysfunction
  • Chronic red blood cell transfusion
  • History of allergy to azithromycin or macrolide antibiotic
  • History of cardiac arrhythmia
  • History of prolonged QT

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Azithromycin prophylaxis
Azithromycin will be supplied as a 250-mg tablet. Participants weighing less than 40 mg will be instructed to take 1 tablet 3 days a week (Monday, Wednesday, and Friday), and participants who weigh more than 40 kg will be instructed to take 2 tablets on the same 3 days per week.
Drug: Azithromycin
Other Names:
  • Zithromax

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame: 48 weeks
48 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
Percent adherence with azithromycin prophylaxis
Time Frame: 48 weeks
48 weeks
Number of participants with improved forced vital capacity (cm3)
Time Frame: 48 weeks
48 weeks
Number of participants with improved forced expiratory volume 1 (cm3/sec)
Time Frame: 48 weeks
48 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Mississippi Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2015

Primary Completion (Anticipated)

December 31, 2017

Study Completion (Actual)

December 31, 2017

Study Registration Dates

First Submitted

November 26, 2015

First Submitted That Met QC Criteria

December 11, 2015

First Posted (Estimate)

December 15, 2015

Study Record Updates

Last Update Posted (Actual)

June 21, 2018

Last Update Submitted That Met QC Criteria

June 19, 2018

Last Verified

June 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SCD_ACS_AZM

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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