Inhaled Mometasone to Reduce Painful Episodes in Patients With Sickle Cell Disease (IMPROVE)

The proposed research is designed to test the global hypothesis that inhaled corticosteroids (ICS), a therapy developed to treat asthma, will prevent vasoocclusive painful episodes in adults with Sickle Cell Disease (SCD) who wheeze, but do not meet criteria for a diagnosis of asthma. The specific aims of this proposal are 1) Conduct a feasibility study - a randomized controlled trial of ICS for adults with SCD who do not meet criteria for a diagnosis of asthma but report recurrent cough or wheezing, 2) Measure the effects of ICS on biological correlates of pulmonary inflammation (as determined by exhaled nitric oxide) and vascular injury (as determined by sVCAM) in SCD, and 3) Compare properties of traditional and Bayesian adaptive clinical trial design for therapeutic trials in SCD in preparation for designing a definitive trial of ICS. These aims have the potential to 1) change the standard of care for individuals with SCD and recurrent cough or wheeze, 2) provide insight into the pathogenesis of non-asthmatic wheezing in SCD and its response to treatment, 3) explore the suitability of innovative clinical trial designs to overcome the challenges that have hindered therapeutic innovation for SCD.

Feasibility is determined by calculating the proportion of randomized participants who complete follow up and a minimum of 30 pain diaries with good adherence to the study medication vs. the number enrolled.

Change in effects of inhaled corticosteroids (ICS) as measured by exhaled nitric oxide levels, which is the primary marker of pulmonary inflammation.

Mean Change in effects of inhaled corticosteroids vascular injury, assessed by biomarker sVCAM as a surrogate for vascular injury.

Mean changes in ASCQ-Me (NHLBI developed a patient-reported Sickle Cell Disease (SCD) quality of life measurement tool) pain impact, at week 20 as compared to baseline. A reduction change on a 100-point scale indicated improved quality of life. ASCQ-Me uses a T-score metric (0-100) in which 50 is the mean of the reference population and 10 is the standard deviation (SD) of that population.

The medication adherence report scale for asthma is a 10 question tool scored between 0 and 5, with full scale from 0 to 25, with higher scores indicating greater adherence

Mean change in patient reported pain NRS score, full scale range 0- 10, higher score indicate more pain

Inclusion Criteria: Age 15 or older Sever SCD phenotypes (Hb SS and Sβthalassemia0) A positive response to cough/wheeze questions Exclusion Criteria: Patient carries a physician diagnosis of asthma Patient is prescribed asthma medications Patient is currently having a painful crisis (as defined by validated pain diary questions) Patient has acute respiratory symptoms Known hypersensitivity to milk proteins Meets criteria for our operational diagnosis of asthma More than 15 ED visits for pain over the preceding 12 months Admitted or discharged from the hospital for SCD pain within the last 7 days

Langer AL, Leader A, Kim-Schulze S, Ginzburg Y, Merad M, Glassberg J. Inhaled steroids associated with decreased macrophage markers in nonasthmatic individuals with sickle cell disease in a randomized trial. Ann Hematol. 2019 Apr;98(4):841-849. doi: 10.1007/s00277-019-03635-9. Epub 2019 Feb 20.

Glassberg J, Minnitti C, Cromwell C, Cytryn L, Kraus T, Skloot GS, Connor JT, Rahman AH, Meurer WJ. Inhaled steroids reduce pain and sVCAM levels in individuals with sickle cell disease: A triple-blind, randomized trial. Am J Hematol. 2017 Jul;92(7):622-631. doi: 10.1002/ajh.24742. Epub 2017 Jun 5.