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Macrolide Therapy to Improve Forced Expiratory Volume in 1 Second in Adults With Sickle Cell Disease

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ClinicalTrials.gov Identifier: NCT02960503
Recruitment Status : Withdrawn (Key personnel moved to new location. Therefore, we had insufficient resources to initiate the trial.)
First Posted : November 9, 2016
Last Update Posted : October 2, 2018
Information provided by (Responsible Party):
Michael DeBaun, Vanderbilt University

Brief Summary:
Sickle cell anemia (SCA) is a life-threatening, monogenic disorder associated with early death when compared to individuals without SCA. Pulmonary complications, namely acute chest syndrome, obstructive lung disease and pulmonary hypertension, are the most common causes of death in patients with SCA. Recent studies suggest that lung specific inflammation is a hallmark of SCA and underlies pulmonary pathology. To date, no therapy has been shown to improve the pulmonary complications of SCA. Macrolides have pleomorphic effects in the lung with improvement in pulmonary function, symptoms and inflammatory markers demonstrated in several inflammatory pulmonary conditions such as cystic fibrosis, asthma, COPD and post-transplant bronchiolitis obliterans. Investigators hypothesize that low dose macrolide therapy is well tolerated and can improve pulmonary function and symptoms in patients with SCA. The objective of this project is to assess the feasibility of macrolides to attenuate or reverse the decrease in %predicted FEV1 in adults with SCA in a single-site, randomized, placebo-controlled feasibility trial.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Drug: Azithromycin Other: Placebo Phase 1 Phase 2

Detailed Description:

Specific aim 1: To determine acceptability of a clinical trial in which participants are randomly allocated to either a placebo or azithromycin 500 mg 3 days a week for 6 months for adults with SCD who have FEV1<80%.

To assess acceptability of this intervention, investigators will measurement recruitment rate, retention and adherence to the study medication. Recruitment will be assessed by proportion of eligible participants that agree to be randomized. Retention will be measured as proportion randomly allocated who complete the trial. Dropout due to toxicity will be categorized using a questionnaire. Medication adherence will be assessed using the previously validated 8 item modified Morisky medication adherence scale (MMAS-8), where responses are categorized: high adherence (8 points), average adherence (6-7 points), and poor adherence (0-5 points). If recruitment rate is < 60%, the retention rate < 80%, or average adherence rate is ≤5 points, the original protocol will be examined and alternative strategies to enhance recruitment, retention, and adherence will be considered.

Specific aim 2: To evaluate the effect of 6 months of low dose azithromycin therapy on FEV1 and respiratory symptoms in patients with SCA. Baseline FEV1 testing with a portable, in-office spirometer will be completed at study enrollment and at the end of the study period (6 months). The previously validated American Thoracic Society (ATS-DLD-78 for adults) questionnaire will also be used to evaluate respiratory symptoms at baseline and end of the study. Under a separate protocol, investigators will calculate the coefficient of variation for FEV1% predicted in adults with sickle cell disease in order to define the within-subject variability for tests of respiratory function in this specific population, which has not been previously described within the medical literature. Calculation of the coefficient of variation for FEV1 % predicted will be essential for the interpretation of clinically and statistically meaningful changes in spirometry for participants who are treated with azithromycin to improve their baseline pulmonary function when compared to controls.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: Macrolide Therapy to Improve Forced Expiratory Volume in 1 Second in Adults With Sickle Cell Disease: a Feasibility Trial
Estimated Study Start Date : September 2016
Estimated Primary Completion Date : October 2018
Estimated Study Completion Date : October 2018

Arm Intervention/treatment
Active Comparator: Treatment arm (azithromycin)
Treatment arm: azithromycin 500 mg three times a week for 6 months
Drug: Azithromycin
Study participants will be randomized to the treatment arm (azithromycin 500 mg three times a week for 6 months).
Other Name: Zithromax, zmax, z-pack

Placebo Comparator: Placebo arm
Control arm: placebo three times a week for 6 months
Other: Placebo
Study participants will be randomized to the control arm (placebo three times a week for 6 months).

Primary Outcome Measures :
  1. Acceptability of the trial will be assessed by the modified Morisky Medication Adherence Scale (MMAS - 8) [ Time Frame: 6 months ]
    Acceptability of the trial will be measured based on three outcomes: recruitment, retention, and adherence rates to therapy. Retention defined as the number of participants that complete the entire study. Recruitment defined as the number of eligible participants that elect to consent to continue with study evaluations. Adherence rate measured based on MMAS score, which was previously validated in children with sickle cell disease (SCD) and scored as follows: high adherence (8 points), average adherence (6 to 7 points) and poor adherence (0 - 5 points).

Secondary Outcome Measures :
  1. Change in FEV1 % predicted in response to 6 months of low dose azithromycin therapy [ Time Frame: 6 months ]
  2. Change in respiratory symptom score (by ATS-DLD-78) in response to 6 months of low dose azithromycin therapy [ Time Frame: 6 months ]
  3. Change in quality of life (by SF-36) in response to 6 months of low dose azithromycin therapy [ Time Frame: 6 months ]
  4. Number of participants with treatment-related adverse events [ Time Frame: 6 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion criteria:

  1. Established diagnosis of sickle cell disease (HbSS, HbSC, HbS/β+, HbS/β0)
  2. Age between 18-50 years
  3. FEV1 < 80% predicted
  4. Willingness to make return visits and availability by telephone for the duration of the study.

Exclusion criteria:

  1. Acute respiratory symptoms
  2. FEV1>80%
  3. Inability to swallow pills
  4. Hypersensitivity to macrolides.
  5. History of cardiac arrhythmias
  6. Prolonged QTc interval (>500 ms) at on baseline EKG
  7. Baseline impairment of hearing by pure tone audiometry defined as patients with age-adjusted hearing thresholds >95th percentile at any one frequency of 500, 1000, 2000 and 4000 Hz.
  8. The presence of a diagnosis other than SCD that results in the patient being medically unstable, or having a predicted life expectancy less than 1 year.
  9. Special patient groups: prisoners, pregnant women, institutionalized patients
  10. Women who are at risk of becoming pregnant during the study, and who refuse to use an acceptable means of birth control (hormonal based oral, intrauterine device or barrier contraception) for the duration of the study.
  11. Patients taking tacrolimus, pimozide, disopyramide, cyclosporine, nelfinavir, bromocriptine, or hexobarbital.
  12. Patients taking any medications that prolong QTc interval.

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): NCT02960503

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United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
Vanderbilt University
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Principal Investigator: Michael R. DeBaun, M.D., M.P.H. Vanderbilt University Medical Center

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Responsible Party: Michael DeBaun, Professor of Pediatrics and Medicine, Vice Chair for Clinical and Translational Research, J.C. Peterson Chair in Pediatric Pulmonology, Director, Vanderbilt-Meharry Center for Excellence in Sickle Cell Disease, Vanderbilt University
ClinicalTrials.gov Identifier: NCT02960503    
Other Study ID Numbers: 161332
First Posted: November 9, 2016    Key Record Dates
Last Update Posted: October 2, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Keywords provided by Michael DeBaun, Vanderbilt University:
sickle cell disease
pulmonary complications
reduced FEV1
lung function
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hematologic Diseases
Genetic Diseases, Inborn
Anti-Bacterial Agents
Anti-Infective Agents