Inhaled Mometasone to Promote Reduction in Vasoocclusive Events 2

Sickle Cell Disease Clinical Trial

— IMPROVE2  

Official title:

Inhaled Mometasone to Promote Reduction in Vasoocclusive Events 2

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03758950
• Other study ID #: GCO 17-1936
• Secondary ID: R01HL142671
• Status: Completed
• Phase: Phase 2
• Start date: November 29, 2018
• Est. completion date: May 31, 2023

Study information

• Verified date: June 2023
• Source: Icahn School of Medicine at Mount Sinai
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: May 31, 2023
• Est. primary completion date: May 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participants age 18 and older with severe SCD phenotypes (Hb SS and Sßthalassemia0):

• 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.

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• Placebo
Once daily inhaled placebo for 48 weeks
• Mometasone
Inhaled Mometasone for 48 weeks (with 4-week washout at study completion)

Locations

Country	Name	City	State
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Mount Sinai St Luke's	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Jeffrey Glassberg	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	LDH level	Change in LDH level at one year compared to baseline. LDH is a marker of hemolysis	Baseline and one year
Secondary	Bilirubin (Direct and Indirect) level	Change in Bilirubin level at one year compared to baseline. Bilirubin measure of hemolysis	Baseline and one year
Secondary	Hemoglobin level	Change in Hemoglobin level at one year compared to baseline. Hemoglobin is a clinical lab test	Baseline and one year
Secondary	Leukocyte Count level	Change in Leukocyte level at one year compared to baseline. Leukocyte is a clinical lab test	Baseline and one year
Secondary	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
Secondary	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
Secondary	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
Secondary	Medication Adherence Self-Report Scale for Asthma (MARS-A)	MARS-A is a 10-item, self-reported measure of adherence	At one year
Secondary	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
Secondary	Spirometry	Change in spirometry at one year compared to baseline. Spirometry is the measure of airflow and lung function.	Baseline and one year
Secondary	Pain Score	Pain score on a zero to ten scale reflects "yesterday's worst pain".	Up to one year
Secondary	Number of ED Visits for SCD Pain	Measure of morbidity and healthcare utilization	One year
Secondary	Number Hospitalizations for SCD Pain	Measure of morbidity and healthcare utilization	One year
Secondary	Number of Observation Unit Admission for SCD Pain	Measure of morbidity and healthcare utilization	One year
Secondary	Number of Overnight Stays for SCD Pain	Measure of morbidity and healthcare utilization	One year
Secondary	Number of Outpatient Infusion Visits for SCD Pain	Measure of morbidity and healthcare utilization	One year
Secondary	Number of Pneumonia Episodes	Measure of morbidity and healthcare utilization	One year
Secondary	Number of ICU Admissions	Measure of morbidity and healthcare utilization	One year
Secondary	Number of Deaths	Measure of disease severity	One year
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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