Inhaled Mometasone to Promote Reduction in Vasoocclusive Events 2

Study Overview
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Brief Summary
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The study team proposes a triple-blind, placebo-controlled, phase II clinical trial of once-daily inhaled mometasone for 48 weeks (with 4-week washout at study completion) in individuals with Sickle Cell Disease (SCD) who report episodic cough or wheeze (ECW) but do not have asthma. Patients will be recruited from and followed in SCD clinics at participating sites. The primary endpoint will be a reduction in sVCAM level of 20% or more in comparison to placebo.

Detailed Description
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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.

Official Title
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Inhaled Mometasone to Promote Reduction in Vasoocclusive Events 2

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Placebo
* Drug: Mometasone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Once daily inhaled placebo | Drug: Placebo<br>* Once daily inhaled placebo for 48 weeks<br>|
| Active Comparator: Mometasone<br>Inhaled Mometasone Furoate 220 mcg DPI | Drug: Mometasone<br>* Inhaled Mometasone for 48 weeks (with 4-week washout at study completion)<br>* Other names: Inhaled Mometasone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Soluble Vascular Cell Adhesion Molecule (sVCAM) level | Change in sVCAM level at one year compared to baseline. sVCAM is a biomarker used as a surrogate for red blood cell (RBC) adhesivity and overall disease severity in SCD. | Baseline and one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reticulocyte Count level | Change in Reticulocyte Count level at one year compared to baseline. Reticulocyte count is a secondary measure of hemolysis. In SCD, it is more reflective of hemolytic burden than any other clinically available laboratory test. | Baseline and one year | 
| Plasma Free Hemoglobin level | Change in Free Hemoglobin level at one year compared to baseline. Free hemoglobin is a direct measure of hemolysis. It is more reflective of hemolytic burden than reticulocyte count but it is not available for clinical use. | Baseline and one year | 
| LDH level | Change in LDH level at one year compared to baseline. LDH is a marker of hemolysis | Baseline and one year | 
| Bilirubin (Direct and Indirect) level | Change in Bilirubin level at one year compared to baseline. Bilirubin measure of hemolysis | Baseline and one year | 
| Hemoglobin level | Change in Hemoglobin level at one year compared to baseline. Hemoglobin is a clinical lab test | Baseline and one year | 
| Leukocyte Count level | Change in Leukocyte level at one year compared to baseline. Leukocyte is a clinical lab test | Baseline and one year | 
| Platelet Count level | Change in Platelet count level at one year compared to baseline. Platelet count is a clinical lab test | Baseline and one year | 
| Exhaled Nitric Oxide | Change in eNO level at one year as compared to baseline. Nitric oxide is a marker of eosinophilic pulmonary inflammation | Baseline and one year | 
| Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) survey | ASCQ-Me is a patient-reported outcome measurement system that evaluates and monitors the physical, mental, and social well-being of adults with sickle cell disease (SCD). ASCQ-Me uses a T-score metric in which 50 is the mean of the reference population and 10 is the standard deviation (SD) of that population. | Baseline and one year | 
| Medication Adherence Self-Report Scale for Asthma (MARS-A) | MARS-A is a 10-item, self-reported measure of adherence | At one year | 
| Brain Natriuretic Peptide | Change in brain natriuretic peptide at one year compared to baseline. Brain natriuretic peptide is a measure of atrial stretch. | Baseline and one year | 
| Spirometry | Change in spirometry at one year compared to baseline. Spirometry is the measure of airflow and lung function. | Baseline and one year | 
| Pain Score | Pain score on a zero to ten scale reflects yesterday's worst pain. | Up to one year | 
| Number of ED Visits for SCD Pain | Measure of morbidity and healthcare utilization | One year | 
| Number Hospitalizations for SCD Pain | Measure of morbidity and healthcare utilization | One year | 
| Number of Observation Unit Admission for SCD Pain | Measure of morbidity and healthcare utilization | One year | 
| Number of Overnight Stays for SCD Pain | Measure of morbidity and healthcare utilization | One year | 
| Number of Outpatient Infusion Visits for SCD Pain | Measure of morbidity and healthcare utilization | One year | 
| Number of Pneumonia Episodes | Measure of morbidity and healthcare utilization | One year | 
| Number of ICU Admissions | Measure of morbidity and healthcare utilization | One year | 
| Number of Deaths | Measure of disease severity | One year | 
| O-Link Inflammation Panel Serum | Change in O-Link Inflammation Panel Serum at one year compared to baseline. A 92 analyte panel of key molecules involved in inflammation | Baseline and one year | 
| O-Link Inflammation Panel Sputum | Change in O-Link Inflammation Panel Sputum at one year compared to baseline. Inflammation panel performed on sputum supernatant will be a measure of pulmonary inflammatory signatures | Baseline and one year | 
| Multiplex Cytokine Panel Serum | Change in Multiplex Cytokine Panel Serum at one year compared to baseline. Key inflammatory mediators including interleukins, selectins, interferon and TNF. | Baseline and one year | 
| Sputum frequency of activated monocytes CyTOF | Change in Sputum frequency of activated monocytes CyTOF at one year compared to baseline. Measure of pulmonary inflammation | Baseline and one year | 
| Sputum Frequency of Aged Neutrophils CyTOF | Change in Sputum Frequency of Aged Neutrophils CyTOF at one year compared to baseline. Measure of pulmonary inflammation | Baseline and one year | 
| Sputum Immune Cell Subpopulations CyTOF | Change in Sputum Immune Cell Subpopulations CyTOF at one year compared to baseline. Frequencies of all immune subpopulations will be calculated to identify pulmonary inflammation signatures. | Baseline and one year | 
| Sputum Immune Cell Subpopulations CyTOF | Change in Sputum Immune Cell Subpopulations CyTOF at one year compared to baseline. Measure of pulmonary inflammation | Baseline and one year | 
| Whole Blood Frequency of Aged Neutrophils CyTOF | Change in Whole Blood Frequency of Aged Neutrophils CyTOF at one year compared to baseline. Measure of pulmonary inflammation | Baseline and one year | 
| Whole Blood Immune Cell Subpopulations CyTOF | Change in Whole Blood Immune Cell Subpopulations CyTOF at one year compared to baseline. Frequencies of all immune subpopulations will be calculated to identify pulmonary inflammation signatures. | Baseline and one year | 
| 6-Minute Walk Test | Change in 6-Minute Walk Test at one year compared to baseline. The distance covered over a time of 6 minutes. Measure of cardiopulmonary exercise reserve. | Baseline and one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle Cell, Inhaled Steroids