Inhaled Mometasone to Promote Reduction in Vasoocclusive Events 2

Dose rationale: Mometasone furoate 220mcg dry powder inhalation is a low-moderate ICS dose
that can be given once daily. Higher doses can have systemic effects and systemic
glucocorticoids can precipitate rebound SCD pain when discontinued.

Adaptive, covariate-balanced randomization: While the sample size of the study will be fixed
at 80 participants, instead of standard blocked or stratified randomization, the study team
will use adaptive covariate-balanced randomization to minimize imbalance of important
covariates. This will reduce the need to use multivariable techniques (which perform poorly
in small samples) to adjust post hoc for differences between treatment groups. Covariates
will include age, use of hydroxyurea, previous rate of Emergency Department (ED) utilization
for SCD pain, and recruitment site.

Follow up Schedule: There will be in-person visits every 8 weeks. In addition, a blinded
research coordinator will contact participants by phone at 2-weeks and 4-weeks after
enrollment and 4-weeks after each in-person follow up to encourage protocol adherence and
collect data about adverse events and healthcare utilization.

Post-protocol observation period: The study will be complete at 48 weeks. A final follow up
visit will occur at 52 weeks (4-weeks after study protocol completed) to collect pain diary
and adverse event data and to identify the proportion of the ICS group who want to continue
ICS. In the event that individuals wish to continue ICS, the PI will contact the
participant's treating physician to discuss.

Data elements: A wide range of clinical and translational data will be collected during the
study. Baseline data will include demographic and clinical variables regarding SCD severity,
previous complications and respiratory surveys. Blood will be collected for standard-of-care
labs and analysis of serum inflammatory cytokines. Pulmonary function testing including
spirometry and Exhaled Nitric Oxide (eNO) will be performed. Health related quality of life
will be collected via ASCQ-Me survey. Patients will also be followed with follow-up phone
calls and prospective chart review for one year to identify hospital visits and other SCD
complications.

Procedures for collection of clinical and laboratory data: Data collection and management:
Case report forms are provided as an appendix. Data will be entered into a REDCap database,
which will be monitored by the Data Coordinating Team (DCT) (led by Co-I Gelijns) for
completion and timeliness.

Inclusion Criteria:

- Participants age 18 and older with severe SCD phenotypes (Hb SS and Sβthalassemia0):

- Do not have asthma (see exclusion criteria)

- Not currently having a painful crisis (as defined by validated pain diary questions)

- Do not have acute respiratory symptoms

- Report of recent ECW (answers "Yes" to any question in Box 1)

- Participant is already medically optimized (i.e. already on maximum dose hydroxyurea
unless contraindicated and not undergoing medication titration).

Exclusion Criteria:

- Participant screens positive for possible undiagnosed asthma (Box 2)

- Pregnant or planning to become pregnant

- > 15 ED visits for SCD pain over the previous 12 months (due to concern for
multi-factorial pain that may be less responsive to SCD therapies)

- Have been discharged from the hospital within the previous 7 days.