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

Sickle Cell Disease Clinical Trial

Official title:

Macrolide Therapy to Improve Forced Expiratory Volume in 1 Second in Adults With Sickle Cell Disease: a Feasibility Trial

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT02960503
• Other study ID #: 161332
• Status: Withdrawn
• Phase: Phase 1/Phase 2
• Start date: September 2016
• Est. completion date: October 2018

Study information

• Verified date: September 2018
• Source: Vanderbilt University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: October 2018
• Est. primary completion date: October 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

Inclusion criteria:

1. Established diagnosis of sickle cell disease (HbSS, HbSC, HbS/ß+, HbS/ß0)

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.

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• Azithromycin
Study participants will be randomized to the treatment arm (azithromycin 500 mg 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).

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Vanderbilt University

Country where clinical trial is conducted

United States, 

References & Publications (10)

Bakheit AH, Al-Hadiya BM, Abd-Elgalil AA. Azithromycin. Profiles Drug Subst Excip Relat Methodol. 2014;39:1-40. doi: 10.1016/B978-0-12-800173-8.00001-5. Review. — View Citation

Boyd JH, Macklin EA, Strunk RC, DeBaun MR. Asthma is associated with increased mortality in individuals with sickle cell anemia. Haematologica. 2007 Aug;92(8):1115-8. — View Citation

Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med. 1997 Sep 11;337(11):762-9. Review. — View Citation

Field JJ, DeBaun MR. Asthma and sickle cell disease: two distinct diseases or part of the same process? Hematology Am Soc Hematol Educ Program. 2009:45-53. doi: 10.1182/asheducation-2009.1.45. Review. — View Citation

Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder WC, Schechter AN, Rodgers GP, Castro O, Ognibene FP. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004 Feb 26;350(9):886-95. — View Citation

Kassim AA, Payne AB, Rodeghier M, Macklin EA, Strunk RC, DeBaun MR. Low forced expiratory volume is associated with earlier death in sickle cell anemia. Blood. 2015 Sep 24;126(13):1544-50. doi: 10.1182/blood-2015-05-644435. Epub 2015 Aug 10. — View Citation

Machado RF, Hildesheim M, Mendelsohn L, Remaley AT, Kato GJ, Gladwin MT. NT-pro brain natriuretic peptide levels and the risk of death in the cooperative study of sickle cell disease. Br J Haematol. 2011 Aug;154(4):512-20. doi: 10.1111/j.1365-2141.2011.08777.x. Epub 2011 Jun 21. — View Citation

Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994 Jun 9;330(23):1639-44. — View Citation

Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson JL, Ip MS, Zheng J, Stocks J; ERS Global Lung Function Initiative. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012 Dec;40(6):1324-43. doi: 10.1183/09031936.00080312. Epub 2012 Jun 27. — View Citation

Vichinsky EP, Neumayr LD, Earles AN, Williams R, Lennette ET, Dean D, Nickerson B, Orringer E, McKie V, Bellevue R, Daeschner C, Manci EA. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000 Jun 22;342(25):1855-65. Erratum in: N Engl J Med 2000 Sep 14;343(11):824. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Acceptability of the trial will be assessed by the modified Morisky Medication Adherence Scale (MMAS - 8)	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).	6 months
Secondary	Change in FEV1 % predicted in response to 6 months of low dose azithromycin therapy		6 months
Secondary	Change in respiratory symptom score (by ATS-DLD-78) in response to 6 months of low dose azithromycin therapy		6 months
Secondary	Change in quality of life (by SF-36) in response to 6 months of low dose azithromycin therapy		6 months
Secondary	Number of participants with treatment-related adverse events		6 months