Macrolide Therapy to Improve Forced Expiratory Volume in 1 Second in Adults With Sickle Cell Disease
| Status: | Withdrawn |
|---|---|
| Conditions: | Anemia |
| Therapuetic Areas: | Hematology |
| Healthy: | No |
| Age Range: | 18 - 50 |
| Updated: | 10/4/2018 |
| Start Date: | September 2016 |
| End Date: | October 2018 |
Macrolide Therapy to Improve Forced Expiratory Volume in 1 Second in Adults With Sickle Cell Disease: a Feasibility Trial
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.
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.
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.
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.
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.
We found this trial at
1
site
1211 Medical Center Dr
Nashville, Tennessee 37232
Nashville, Tennessee 37232
(615) 322-5000
Principal Investigator: Michael R. DeBaun, M.D., M.P.H.
Phone: 615-322-5000
Vanderbilt Univ Med Ctr Vanderbilt University Medical Center (VUMC) is a comprehensive healthcare facility dedicated...
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