Conditions: Sickle Cell Disease
Keywords: Sickle Cell Disease Pain Crisis Painful Crisis Sickle Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 54
Healthy volunteers: no

Brief summary:
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.

Detailed description:

Arms:
arm 1: 1 puff daily (220mcg) for 16 weeks arm 2: 1 puff daily for 16 weeks. Training inhaler that does not contain any medication (placebo).

Interventions: intervention 1: Mometasone Furoate intervention 2: Placebo
Intervention descriptions: intervention 1: inhaled cortico-steroid (ICS) with a dosage of 220mcg once daily for 16 weeks intervention 2: placebo training inhaler with the same instructions as the experimental group.

Protocol document:
Prot_SAP_000.pdf: 
Inhaled Mometasone to Promote Reduction Of Vaso-occlusive Events Trial 
(IMPROVE Trial)
A feasibility study
NCT02061202
Version Date: 11-18-2015


Supplement 1: Study protocol and schedule of protocol changes 
•
12/24/2013: Protocol modified to add and remove study personnel
•
February, 2014: First participant enrolled
•
3/11/2014: Minor changes to case report forms
•
6/30/2014: Add investigator signatures to case report forms
•
9/16/2014: Draw an additional 5-10 cc of blood at study entry and 8-weeks to performed cell-based
assays of immune activation
•
5/11/2015: Clarify color of tubes for blood collection
•
9/18/2015: Change metrocard incentive to $11 from $10
•
11/18/2015:
1.
The medication adherence cutoff for inclusion in per-protocol analyses was changed from
80% to 70%
2.
The original protocol included non-adherent individuals in the intent to treat analyses but
did not follow them after 8-weeks (i.e. after follow up questionnaires, clinical data,
spirometry, eNO and blood were collected). The protocol was modified to continue
following non-adherent individuals up to 16 weeks to evaluate strategies to improve
medication adherence.
•
October, 2016: Data collection completed


Manual of Operating Procedures 
Inhaled Mometasone to Promote Reduction Of Vaso-occlusive Events 
Rev 11-18-15 
Inhaled Mometasone to Promote Reduction Of Vaso-occlusive Events Trial 
(IMPROVE Trial) 
A feasibility study 


Manual of Operating Procedures 
Inhaled Mometasone to Promote Reduction Of Vaso-occlusive Events 
Rev 11-18-15 
 
 
 
Inhaled Mometasone to Promote Reduction Of Vaso-occlusive Events Trial 
(IMPROVE Trial) 
 
 
Jeffrey A. Glassberg MD, MA FACEP 
Principal Investigator 
Icahn School of Medicine at Mount Sinai 
1 Gustave Levy Place 
Box 1620 
New York, NY 10029 
Phone: (212) 824-8056 
Fax: (212) 426-1946 
Email: Jeffrey.glassberg@mssm.edu 
Alexa Punzalan 
Senior Research Coordinator 
Icahn School of Medicine at Mount Sinai 
1 Gustave Levy Place 
Box 1620 
New York, NY 10029 
 
 
Aria Mattias 
Research Coordinator 
Icahn School of Medicine at Mount Sinai 
1 Gustave Levy Place 
Box 1620 
New York, NY 10029 
 
 
Gary Winkel 
Senior Statistician 
Icahn School of Medicine at Mount Sinai 
East Building 2-70 
New York, NY 10029 
 
Christina Gestal 
Research Coordinator 
Icahn School of Medicine at Mount Sinai 
1 Gustave Levy Place 
Box 1620 
New York, NY 10029 
 
 
 
 
Cyndi Gonzalez 
Research Coordinator 
Icahn School of Medicine at Mount Sinai 
1 Gustave Levy Place 
Box 1620 
New York, NY 10029 
 
 
Jena Simon, MS, FNP-BC, RN-BC 
Study Nurse 
1 Gustave L. Levy Place 
Box 1495 
New York, NY 10029 
 
 


Manual of Operating Procedures 
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TABLE OF CONTENTS 
 
1.0 
Study Roster…………………………………………………………………………………………… 
1 
1.1 Principal investigator 
1.2 Research coordinators 
1.3 Advisory board 
1.3.1 Personnel 
1.3.2 Meeting Schedule 
1.4 Data Safety and Monitoring Board 
1.4.1 Personnel 
1.4.2 Meeting Schedule 
1.4.3 DSMB Responsibilities 
1.5 1.6 Analysis Team 
2.1 
Study Organization and Responsibilities………………………………………………………… 
4 
2.2 Clinical Coordinating Center 
2.3 Statistical Coordinating Center 
2.2.1 IMPROVE trial organization chart 
3.0 
Study Overview……………………………………………………………………………………….. 
8 
4.0 
Storage and study materials………………………………………………………………………... 
8 
4.1 The IMPROVE research cart 
4.2 Study medication 
5.1 
Recruitment, screening, and eligibility procedures……………………………………………. 
8 
5.2 Screening potential participants in the ED 
5.2.1 Overview 
5.2.2 Eligibility for screening ED patients 
5.2.2.1 Inclusion criteria for screening 
5.2.2.2 Exclusion criteria for screening 
5.2.3 ED screening procedure 
5.3 Pre-screening and screening in clinic 
5.3.1 Identification of eligible participants 
5.3.2 Eligibility 
5.3.2.1 Inclusion criteria for randomization 
5.3.2.2 Exclusion criteria for randomization 
5.3.3 Procedure 
5.3.4 Randomization and Enrollment 
5.3.4.1 Overview 
5.3.4.2 Informed consent 
5.3.4.3 Baseline data collection 
5.3.4.4 Urine and serum collection and processing 
5.3.4.5 Pulmonary function testing 
5.3.4.6 Measurement of Exhaled Nitric Oxide NIOX Mino 
5.3.4.7 Randomization 
 
Page 
6.0 
Telephone follow up (week 2)………………………………………………………………………. 
13 
6.1  Overview 
7.0 
Telephone follow up (week 4) ………………………………………………………………………. 
13 
7.1  Overview 
8.0 
In-person follow up (week 8) …………………………………………………………………………  14 
8.1 Overview 
8.2 Intake 
8.3 Medication refills 
8.4 Criteria to remain in the study 
8.5 Data collection 


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8.5.1 Questionnaire 
8.5.2 Serum collection 
8.5.3 Pulmonary function testing 
8.5.4 Exhaled nitric oxide 
8.6 Pain diary processing 
8.7 Financial incentives/additional pain diaries 
Table 1 – Timeline of financial incentives 
8.8 Discharge and follow up arrangements 
9.0 
Telephone follow up (week 12) ………………………………………………………………………. 16 
9.1  Overview 
10.0 
End of study visit (week 16) …………………………………………………………………………..  16 
10.1 Overview 
10.2 Intake 
10.3 Collection of study medication 
10.4 Procedures for individuals who wish to continue study medication 
10.5 Data collection 
10.6 Pain diary processing 
10.7 Financial Incentives/additional pain diaries 
10.8 Discharge and follow up arrangements 
11.0 
Post-protocol observation period visit (week 20)…………………………………………………  17 
11.1 Overview 
11.2 Intake 
11.3 Procedures for individuals who wish to continue study medication 
11.4 Data collection 
11.5 Pain diary processing 
11.6 Financial incentives 
11.7 Discharge and follow up arrangements 
12.0 
Procedures for loss of study medication…………………………………………………………..   18 
13.0 
Data management procedures………………………………………………………………………. 
18 
13.1 Study logs 
13.2 Case report forms 
13.3 Database management 
14.0 
Data Analyses ………………………………………………………………………………………….. 
18 
14.1 Primary and Secondary Outcomes 
14.2 Potential outcomes for a definitive multi-center trial 
14.3 Aim 2: Primary and Secondary Outcomes 
14.4 Data Analysis 
14.5 Preliminary Data Analysis 
14.6 Exploration of potential definitive outcomes 
14.7 Sample Size Analysis 
14.8 Data Analysis 
14.9 Sample Size Analysis 
15.1 
Schedule of oversight procedures ………………………………………………………………… 
20 
15.2 DSMB meetings 
15.3 FDA annual reports 
16.0 
Provisions for research related injury…………………………………………………………….. 
20 
17.0 
Procedures for study withdrawal…………………………………………………………………… 
21 
18.1 
Appendices 
18.2 Appendix 3 – HIMC SOPs (Plasma Collection, Paxgene, and Flow Cytometry……… 
22 
18.2 Case report forms…………………………………………………………………………………  38 
CRF 1: Contact Info…………………………………...………………………………  38 
CRF 2: Adverse Events Form……………………......………………………………  39 


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CRF 3: Screening Questionnaire………..…………...………………………………  41 
CRF 4: Initial Intake Form………………………...……………..…………………… 43 
CRF 4a: Spirometry and Exhaled Nitric Oxide at Intake……………………..…… 51 
CRF 4b: Laboratory Results at Intake……..………...…………………………...… 53 
CRF 4c: Serum Results at Intake………………….....……………………………... 55 
CRF 5: Week 8 Data Collection………………………...…………………………… 56 
CRF 5a: Spirometry and Exhaled Nitric Oxide at 8 Weeks………………….…… 64 
CRF 5b: Laboratory Results at 8 Weeks…………………………………………… 66 
CRF 5c: Serum Results at 8 Weeks………………………...……………………… 68 
CRF 6: End of Study Questionnaire………………...……………………………… 69 
CRF 7: Post Protocol Questionnaire…………………………..……………………   78 
CRF 8: 8 Week Adherence Status……………...…………………..………………   83 
CRF 9: 16 Week Adherence Status………………...………………………………   70 
CRF 10: ED Screening Log………..………………...……………………………… 85 
CRF 11: Loss of Study Medication……………….....……………………………… 86 
CRF 12: Death………………………………………...……………………………… 87 
CRF 13: Study Medication Temp/Humidity Log………………………………….      88 
 
18.3 Educational materials………………………………………………..……………………………… 89 
Protocol Orientation Module A…………………………...…………………………… 90 
Protocol Orientation Module B………………………...………………………………  97 
 
18.4 Pain Diary……………………………………………………………………………………………… 102 


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Study Personnel (see staff signature log and site delegation tasks) 
1.1 Principal investigator 
 
Jeffrey A. Glassberg MD, MA FACEP 
Principal Investigator 
Icahn School of Medicine at Mount Sinai 
1 Gustave Levy Place 
Box 1620 
New York, NY 10029 
Phone: (212) 824-8056 
Fax: (212) 426-1946 
Email: Jeffrey.glassberg@mssm.edu 
1.2 Research coordinators 
Alexa Punzalan 
Senior Research Coordinator 
Icahn School of Medicine at Mount Sinai 
1 Gustave Levy Place 
Box 1620 
New York, NY 10029 
 
 
 
Aria Mattias 
Research Coordinator 
Icahn School of Medicine at Mount Sinai 
1 Gustave Levy Place 
Box 1620 
New York, NY 10029 
 
 
 
Cyndi Gonzalez 
Research Coordinator 
Icahn School of Medicine at Mount Sinai 
1 Gustave Levy Place 
Box 1620 
New York, NY 10029 
 
 
 
 
 
Christina Gestal 
Research Coordinator 
Icahn School of Medicine at Mount Sinai 
1 Gustave Levy Place 
Box 1620 
New York, NY 10029 
 


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Cindy Clesca 
Research Coordinator 
1 Gustave Levy Place 
Box 1620 
New York, NY 10029 
 
 
 
1.3 Advisory board – 
1.3.1 Personnel 
Lynne Richardson 
K23 Mentor 
Professor & Vice Chair of Emergency Medicine 
Professor of Health Evidence and Policy 
1 Gustave Levy Place 
Box 1620 
New York, NY 10029 
 
 
Michael DeBaun 
Sickle Cell Mentor 
Professor of Pediatrics and Meidicine 
J.C. Peterson Chair in Pediatric Pulmonology 
Director, Vanderbilt-Meharry Center for Excellence in Sickle Cell Disease 
2200 Children’s Way, 
 
Nashville, TN 37232 
 
Barry Coller 
T1 mentor 
Physician-in-Chief, Vice Prsident for Medical Affairs, Rockefeller University 
1230 York Ave. 
New York, NY 10065 
 
Charles DiMaggio 
Biostatistician 
Associate Professor at CUMC of Epidemiology 
622 West 168 St. 
 
New York, NY 10032 
 
Robert Strunk 
Pulmonary Expert 
Donald Strominger Professor of Pediatrics, Pediatric Allergy, Immunology and 
Pulmonary Medicine and Professor of Pediatrics 
Washington University School of Medicine 
660 S. Euclid Avenue, Campus Box 8116 
St. Louis, MO  63110 
 
Juan Wisnivesky 


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Pulmonary Expert 
Professor of Medicine, General Internal Medicine at 
Icahn School of Medicine at Mount Sinai 
 
 
 
New York, NY 10029 
 
1.3.2 Meeting Schedule 
Advisory board meetings will occur quarterly 
 
1.4 Data Safety and Monitoring Board 
1.4.1 Personnel 
 
MSSM Principal Monitor: Jeffrey Glassberg (PI) 
Last Name: Glassberg 
First Name: Jeffrey 
Academic Title: Assistant Professor 
Department: Emergency Medicine and Internal Medicine (Division of Hematology and 
Medical Oncology) 
Mailing Address: 1 Gustave Levy Place Box 1620, New York, NY 10029 
Phone: 212-824-8056 
Fax: 212-426-1946 
E-mail: jeffrey.glassberg@mssm.edu 
 
MSSM Additional Monitor: Lynne Richardson 
Last Name: Richardson 
First Name: Lynne 
Mailing Address: 1 Gustave Levy Place Box 1620, New York, NY 10029 
Academic Title: Vice Chair for Academic Research and Community Programs 
Department: Emergency Medicine 
 
 
 
 
Charles DiMaggio PhD 
Associate Professor at CUMC of Epidemiology 
622 West 168 St. 
 
New York, NY 10032 
 
Robert Strunk MD 
Donald Strominger Professor of Pediatrics, Pediatric Allergy, Immunology and Pulmonary 
Medicine and Professor of Pediatrics 
Washington University School of Medicine 
660 S. Euclid Avenue, Campus Box 8116 
St. Louis, MO  63110 
 
Juan Wisnivesky MD 
Professor of Medicine, General Internal Medicine at 
Icahn School of Medicine at Mount Sinai 
 
 
New York, NY 10029 


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1.4.2 Meeting Schedule 
The DSMB will meet prior to subject enrollment and data collection and will meet at 6 
month intervals thereafter 
1.4.3 DSMB responsibilities 
The DSMB will report Adverse Events (AEs) to the Mount Sinai Institutional Review 
Board, the funding I/C, the NIH Office of Biotechnology Activities (OBA), and the Food and 
Drug Administration (FDA) in accordance with Investigational New Drug (IND) regulations. 
The responsibilities of the DSMB will include: 1) overseeing the study’s progress, 2) 
approving alterations or amendments to the study protocol, 3) monitoring safety and 
reviewing serious adverse events (SAE) which includes: death, intubation for acute chest 
syndrome, intensive care unit admission, or pulmonary infection, 4) overseeing data 
quality, 5) reviewing the interim analyses and recommending early trial cessation if 
indicated. The PI will be responsible for providing the DSMB with all necessary 
information. 
1.5  Analysis Team 
Gary Winkel PhD 
Research Professor, Oncological Sciences, Icahn School of Medicine at Mount Sinai 
Icahn School of Medicine at Mount Sinai 
East Building 2-70 
New York, NY 10029 
 
 
2.1 
Study organization and Responsibilities 
2.2 
Clinical coordinating center 
 
The IMPROVE trial Clinical Coordinating Center (CCC) is directly responsible for the monitoring 
and oversight of all fiscal, regulatory, clinical and other general administration needed to 
centralize and coordinate the research endeavors of the IMPROVE trial. The CCC is located at 
the Icahn School of Medicine at Mount Sinai (ISMMS) and is led by the Study PI, Jeffrey A. 
Glassberg MD, MA. Under the PI supervision the senior research coordinator (SRC) will assist 
with the responsibilities of the CCC. 
 
The responsibilities of the CCC will include: 
• 
protocol and manual of operations development and amendments 
• 
facilitating and monitoring protocol conduct 
• 
overseeing regulatory compliance 
• 
monitoring of adverse effects and events 
• 
assuring quality control via site audits 
• 
providing annual and quarterly reports on the progress of the IMPROVE Trial 
• 
electing topics for investigation 
• 
participating in the analysis and interpretation of data 
• 
manuscript preparation and prioritization via the IMPROVE Trial Publication Policy 
• 
plan and organize investigator and oversight meetings 
• 
coordinate all NIH requirements related to the grant 
 
2.3 
Statistical coordinating center (SCC) 
 
Collection and analysis of data generated for the IMPROVE trial will be coordinated by the PI 
and research coordinators (RCs) and will leverage the resources of the biostatistics, 


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epidemiology, and research design (BERD) program at ISMMS to monitor data collection. 
Responsibilities of the SCC will include: 
 
• 
Preparation of study documents 
SCC staff will develop: Protocol, Manual of Operating Procedures (MOP), case 
report forms (CRFs), and QxQs (question by question), which give the details on 
answering the questions on every CRF).  Materials given to participants (brochure/copy 
of consent form) will not mention the study acronym “IMPROVE” to avoid suggestive 
influence of the title. 
 
• 
Statistical design and sample size 
SCC statisticians developed the statistical design for the study, including the primary 
outcome, sample size, randomization strategy, primary analysis strategy, and the 
complete analysis plan. 
 
• 
Training site personnel 
SCC staff has have trained site personnel in all aspects of the study related to: 
details of the study protocol, data collection procedures, screening and randomization 
procedures, submitting forms to the SCC, laboratory preparation procedures, and 
responding to queries from the SCC. SCC staff will also monitor each site to assure that 
the site coordinators have completed the required training. 
 
• 
Receipt and processing of study forms at the SCC 
SCC staff have designed and implemented the data management system for the 
study, including: electronic data entry, comprehensive editing of the data and preparation 
of protocol adherence aids, and data extraction for analyses related to                 
research objectives. Data are submitted to the SCC through REDCap, a web-based data 
entry system. All hardcopy CRF’s are maintained in a locked cabinet in a locked room. 
Once hardcopy enters this storage facility, it does not leave. Data are comprehensively 
edited once received at the SCC, prior to insertion into the main study database. Edit 
queries are resolved within a few days with the PI. The PI electronically signs off on all 
case report forms in REDCap before they are finalized. SCC staff also enforces patient 
confidentiality and privacy rules so that PHI data are not shared inappropriately and so 
that data are protected by multiple layers of security. 
 
• 
Monitoring study progress and data quality 
SCC staff ensures that clinic site staff are properly trained, that performance of the 
required procedures are monitored, and that deviations from the protocol or from study 
norms are investigated. Routine site monitoring reports, including patient recruitment, 
performance of follow-up visits, and protocol compliance, will be produced at regular 
intervals.  For spirometry, the SRC’s past 10 PFT results will be reviewed to ensure 
reproducibility of results. 
 
• 
Quality assurance procedures 
SCC staff will conduct quality assurance audits for every 5 participants enrolled in  
the study. In addition, quality assurance procedures and programs will be developed and 
implemented for laboratory determinations, for data collection, and for data entry. 
 
• 
Randomization 
SCC staff have developed and implemented an adaptive, biased coin, covariate 
balanced randomization algorithm. The algorithm is implemented using a windows 
laptop running the program ‘R’ which will be carried on the IMPROVE research cart. 


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After screening for eligibility is complete, participants will be randomized. The 
Randomization algorithm will balance participants based on whether or not they take 
hydroxyurea and by the number of ED visits for pain during the preceding year (this 
variable will be trichotomized: 0-5, 6-10, 11-15). 
 
• 
Data and Safety Monitoring Board (DSMB) functions and reports 
SCC staff will prepare reports for the DSMB and will respond to ad hoc queries from 
the DSMB. SCC staff developed the study monitoring plan, which indicates when interim 
monitoring of the efficacy outcomes will be performed, how adverse events will be 
reported, as well as the content of the DSMB reports. The DSMB reports will include 
tabulations and graphical presentation of administrative data (e.g., recruitment, 
compliance with therapy schedule, completion of follow-up procedures, and submission 
of data to the SCC), efficacy data (e.g., primary and secondary outcomes of the study, 
as required by the monitoring plan), and safety data (e.g., the occurrence of adverse 
events and serious adverse events). 
 
• 
Statistical analysis plan 
SCC staff developed the statistical analysis plan, which indicates, in detail, the main 
analysis for the primary outcome (including intention-to-treat analyses), secondary 
analyses, and analyses of the secondary and safety outcomes. In addition, the plan 
includes the frequency of DSMB reports, and how missing data will be handled. 
 
• 
Collaboration in study publications 
SCC staff will collaborate in all study publications, providing statistical analysis, 
preparing the statistical methods and results sections of manuscripts, and preparing 
camera-ready tables and graphs. SCC staff will also participate in the development and 
review of abstracts for presentations and in the review of the statistical analysis for 
ancillary publications. 


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2.2.1 IMPROVE trial organizational chart 
 
 
 
 
Clinical and Statistical Coordinating Center 
ISMMS 
Chair – Jeffrey A Glassberg MD, MA 
SRC – Alexa Punzalan 
DSMB 
Principal Monitor – Jeffrey A Glassberg MD, MA 
Additional Monitor – Lynne Richardson, MD 
Charles DiMaggio PhD 
Robert Strunk, MD 
Juan Wisnivesky MD, MSc 
Clinical Site 
ISMMS New York, NY 
PI – Jeffrey A Glassberg MD, MA 
SRC – Alexa Punzalan 


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3.0 
Study overview 
We will conduct a randomized, double blind, placebo-controlled, feasibility study of mometasone furoate, an 
inhaled cortico-steroid (ICS), for 16 weeks in individuals with SCD and recurrent cough or wheezing who do 
not meet clinical criteria (derived specifically for individuals with SCD) for a diagnosis of asthma. Participants 
will be enrolled when they are pain free and have no acute respiratory symptoms. The sample size will be 45 
participants, aged ≥15, with 2:1 allocation of drug to placebo. Feasibility will be determined by the proportion of 
individuals successfully randomized who maintain good adherence and complete at least 30 pain diaries vs. 
the total number enrolled. 
4.1 
Storage of study materials 
4.2 
The IMPROVE research cart 
 
A mobile research cart will be maintained by the SRC. The research cart is equipped with a laptop, 
FVL machine (spirometry machine) with 3L syringe, disposable mouth pieces and nose plugs; mini 
centrifuge with micro tubes and pipettes. The research cart will also be stocked with study 
medication packets (closed envelopes which contain training materials and study medication or 
placebo), study binders (study logs, enrollment paperwork), and the NIOX MINO exhaled nitric 
oxide measuring device. 
 
4.3 
Study medication 
 
As already approved by the ISMMS research pharmacy, study medication will be stored in Dr. 
Glassberg’s office in a locked cabinet. Thermostat will be set at all times to maintain acceptable 
storage temperature (59-86 °F). Throughout the week, temperature and humidity (current readings 
as well as min and max for both) will be logged daily on the study medication temperature log 
sheet (CRF13) using a Fisher Scientific digital Traceable Thermometer/Clock/Humidity monitor. 
Over the weekend, min and max temperature and humidity will be logged on the Monday following. 
Min and max temperatures are stored after the memory is cleared (once each day). Dr. Glassberg 
packages, dispenses, and maintains accountability for all study medication is assisted by the 
unblinded RC in packaging and distribution. 
Study packets for randomization will be made from sealable envelopes. Each packet will contain 
sufficient medication for 8 weeks (one 60-dose mometasone twisthaler or one placebo metered 
dose inhaler MDI). Packets containing active medication will include ‘protocol orientation module A’ 
(a document that has training and usage instructions for the mometasone twisthaler). Packets 
containing placebo will contain ‘protocol orientation module B’ (a document that has training and 
usage instructions for the placebo inhaler). Each packet will also include 60 pain diaries. Packets 
will then be sealed and labeled with a code. The code will indicate which treatment arm the packet 
corresponds to. The unblinded RC will have access to a master list that reveals the coding scheme, 
SRC and PI will not have access to this list. 
In the event that Dr. Glassberg is not present during study recruitment/enrollment, licensed nurse 
practitioner Jena Simon will be present to oversee dispensation of study drug or placebo. 
 
5.1 
Recruitment, screening and eligibility procedures: 
5.2 
Screening potential participants in the ED 
5.2.1 Overview 
 
As stated in the protocol, in addition to clinic, potential participants will be identified in the ED. 
 
In the ED, subjects will be identified by the PI or RC. The RC will ask the treating physician for 
permission to approach the patient. The RC will approach the patient in a private area conducive 
to private conversation (drawing the curtain in the ED).  If the patient meets eligibility criteria (see 
5.1.2) and expresses interest in participating in the study, the RC will take the patient’s contact 
information (two phone numbers, address and email) to contact the patient at a later date to 


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discuss the study in greater detail and assess interest in participation. The patients contact 
information will be recorded in CRF 1 – Contact Information. The patient will be given information 
about the study (study brochure), and informed that there will be financial incentives for 
participating (metro-cards and gift cards at each visit). 
 
 
5.2.2 Eligibility for screening ED patients 
5.2.2.1 Inclusion criteria for screening 
• 
Age 15 and older 
• 
A history of SCD 
5.2.2.2 Exclusion criteria for screening 
• 
Unable to communicate 
• 
Altered mental status 
• 
Unstable vital signs 
• 
The physician asks you not to approach the patient 
• 
Pregnant 
 
5.2.3 ED screening procedure 
• 
. 
• 
The RC will monitor the tracking board for indicators that a patient has SCD (chief complaint 
contains the word ‘sickle’ or chief compliant contains the word ‘crisis’) 
• 
Once a patient has been identified, the RC will ask the treating physician for permission to 
approach the patient. 
• 
The RC approaches patient in an area conducive to private conversation (private room or 
curtain pulled). 
• 
RC explains that they are collecting contact information for people interested in participating 
in a clinical trial of a treatment for SCD. 
• 
If the patient expresses interest, RC records contact information on CRF 1 – Contact Info. 
• 
Completed CRF’s are stored in the IMPROVE folder in a locked cabinet in Dr. Glassberg’s 
office. 
• 
The RC will enter CRF data into an encrypted Microsoft Access database and make weekly 
calls to prospective participants to arrange for an initial visit at the SCD clinic where the 
patient may be enrolled. In the event that the patient does not wish to follow in clinic but 
wants to participate in the study, a non-clinical visit in a private consultation room in the ED 
will be arranged. 
• 
The RC will record de-identified information about each individual on CRF 10. 
• 
The database will be destroyed when the study is complete. 
 
5.3 Pre-screening and screening in clinic 
5.3.1 Identification of eligible participants 
 
When patients are greeted upon arrival to the SCD clinic, the RC will monitor the EPIC tracking 
board to identify patients who are above the age of 15 that have SCD. The RC will approach 
patients while they are in the waiting room to ask if they are interested in having a private 
discussion about a research study. Interested individuals will be brought to a private 
consultation area for screening and enrollment. 
5.3.2 Eligibility 
5.3.2.1 Inclusion criteria for randomization 
• 
Age 15 and older 
• 
Severe SCD phenotypes (Hb SS and Sβthalassemia0) 
• 
A positive response to cough/wheeze questions in CRF 3 – Screening Form. 


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5.3.2.2 Exclusion criteria for randomization 
• 
Patient carries a physician diagnosis of asthma 
• 
Patient is prescribed asthma medications 
(Note: short acting beta agonists will not be considered as part of the list of “asthma 
medications” that are grounds for exclusion from the study. Classes of asthma 
medications that will still constitute grounds for exclusion include: inhaled steroids, long 
acting beta agonists, leukotriene modifying drugs, and IgE targeting monoclonal 
antibody therapies) 
• 
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 (CRF 3 – Screening Form) will 
also be excluded. 
• 
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 
• 
Patient is pregnant or planning to become pregnant during the duration of the study. 
 
5.3.3 Procedure 
 
If the participant expresses interest in participating in the study, the RC will bring the patient to a 
private area and ask questions in CRF 3 – Screening Form. Completed CRF 3 forms will be 
destroyed once the patient’s eligibility has been determined. If eligibility criteria are met on CRF 
3 and the patient continues to express interest, the RC will then check EPIC for documentation 
that the patient has Hb SS or Sβthalassemia0 and that the individual is not prescribed any 
asthma medications. If these criteria are met, the patient will be randomized. 
 
 
5.3.4 Randomization and Enrollment 
5.3.4.1 Overview 
Individuals who meet inclusion/exclusion criteria will then be consented and randomized. 
The enrollment procedure is designed to maintain blinding of the participant, the PI and the 
senior RC. One RC will be unblinded (RC2) for purposes of introducing the study 
medication, training in proper use of the medication and refilling medication if the participant 
loses their medication. 
5.3.4.2 Informed consent 
 
Since an informed consent is a document required by law, this standard will require 
significant attention to all steps as set forth by good clinical practices. To ensure that 
patients’ rights are protected and that all study participants receive, read, have explanation 
of and sign an informed consent prior to enrolling in any study or protocol, the following 
steps will be followed. The principal investigator or designee must: 
 
1. Know all of the elements of informed consent 
2. Explain to the patient/parent the importance of and reasons for obtaining informed 
consent 
3. Provide the patient/parent a quiet, undisturbed area for him/her to read the informed 
consent. 
4. If the patient/parent is unable to read, then read the consent to him/her slowly. 
5. After the patient/parent completes the reading of the consent, provide adequate time for 
him/her to ask any study or consent related questions of the study doctor and or study 
nurse. 


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6. Document these questions and answers in the progress notes of the chart along with a 
notation that the consent was read and reviewed by the patient/parent, that the 
patient/parent was provided a signed copy, as well as the date and time the informed 
consent was signed.. 
7. The patient/parent should then sign and date the consent in all areas appropriate with 
BLACK ink only. 
8. Witness the patient/parent signing the informed consent, then sign and date in the 
witness space of the consent. 
9. Give the patient/parent a signed photocopy of the informed consent. 
10. Retain the original signed informed consent document in the research chart with a copy 
in the patient’s outpatient chart. 
11. If the patient/parent must ever sign a revised/amended consent for this study, repeat this 
process.  DO NOT dispose of any prior consent(s).  They all remain a part of the record. 
5.3.4.3 Baseline data collection 
 
After the participant has completed the informed consent process, CRF 3 will be completed 
again to ensure the patient’s eligibility to be a part of the study. Then the senior RC will 
administer CRF 4 the baseline data collection form. 
 
5.3.4.4 Urine and serum collection and processing 
 
The patient will then go to phlebotomy to have labs drawn as part of standard care for their visit. 
Research tubes will be supplied to the phlebotomist to be drawn in addition to standard care labs. A 
sterile cup will be provided for urine collection. Processing of samples will be done according to the 
following protocol. Samples are to be stored in the Annenberg building in Tom Moran’s lab 
(Annenberg Building Floor 18 Room  18-08, 1468 Madison Avenue). 
 
In clinic: 
Collect blood in one gold top serum tube (~5mls blood), one paxgene tube (2.5ml blood), 
and two green top tubes (~5.5ml blood each).  All samples will be sent for processing de- 
identified.  The gold top tube is labeled with the date, patient ID and inverted 2x and stored 
in a portable ice chest for up to 6 hrs until transfer to lab for processing. The PAXgene tube 
blood will be labeled with by the study name, followed by the ID number starting with 7001 
(and so on for consecutive participants) and V1 or V2 to designate the time point collected 
(V1at baseline and V2 at 8 Weeks). The PAXgene will be drawn vertically to allow blood to 
flow into the tube to exactly 2.5ml and inverted X8-10 after collection. The green top tubes 
will be labeled in the same manner as the PAXgene tube and inverted X5 after collection. 
The PAXgene tube can be kept at room temperature for up to 6 hours before transport at 
end of clinic day.  The green top tube can be kept at room temperature for up to 30 minutes 
before transport to HIMC (Hess 5th Floor Rooms 310/313) for processing by HIMC staff. 
 
For urine, instruct patient to sample clean catch in cup. Cup will be sealed, labeled, bagged 
and stored in a portable ice chest until processed. 
In lab: 
Blood: Spin at 2000 RPM, 5 mins, and aliquot serum into 4 labeled cryovials. Store at -80oC. 
Label as: 
Date Patient ID 
Serum (or Urine) 
PI: J. Glassberg, MD 
 
Urine:  Transfer to vacutainer to centrifuge as above. 
Aliquot in labeled cryovials and store at -80. 


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(For HIMC SOP see appendix) 
5.3.4.5 Pulmonary Function Testing 
 
Steps for PFT Testing 
Summary: Calibrate the device before testing on patients for the day. 
1. Calibration – typically once a day 
a. Go to Calibration 
b. Run QC Spirometry 
i. Connect the 3-L syringe to the blue adaptor tube. Connect the other end of 
the blue tube to the narrower side of the mouthpiece, which then connects to 
the FVL. Make sure the syringe is closed. Click Done. 
ii. The device will check for zero flow. Do not pump the syringe at this time. 
iii. Following the instructions, pull the syringe to fill with air, then push at different 
flow rates: 
1. 2 times at the low flow rate target, at least 1 time at each of the higher 
flow rates 
c. Troubleshooting Failed ATS (failing QC) 
i. Redo QC Spirometry. 
ii. If failed again, click the red button at the lower left corner of the calibration 
home screen (diagnostics and device configuration). 
iii. Go to Create New Span Factor  Span pneumotach F/V  With syringe 
connected, aim for targets 
iv. Once ATS passed, click the red button (diagnostics and device configuration) 
and perform QC again. 
1. If QC still fails, then recalibrate by building a new table under 
diagnostics and device configuration. 
2. Run Test 
a. Create a patient 
i. Go to New Patient at the right of the Patients home screen. 
ii. Fill in Identification and Information 
iii. Save. 
iv. For each test, fill in Biometrics, Smoking, Referral, etc. 
v. Patients for the day can be found in the scroll down at the top of the program. 
Patients can also be searched under Find at the top or under Patients. 
b. Go to Run Test on the left or on the middle right of the patients home screen. 
i. Enter Environmental Data (default values may be okay depending on study) 
ii. Make sure patient’s mouthpiece is attached to the FVL. 
iii. Go to Start Pre Effort and allow device to verify zero flow. Make sure patient 
is not breathing into mouthpiece 
iv. Ask patient to wear nose clip and to insert the mouthpiece, creating an 
airtight seal with the mouth and resting the tongue under the opening of the 
mouthpiece. 
v. After at least two tidal waves of normal breathing, tell the patient to take a 
deep breath on the next inhale and to blast everything out as hard and fast as 
possible. 
vi. Encourage the patient to continue pushing out air for at least 6 seconds. 8 
seconds recommended. Watch the Forced Expiratory Time (FET) dial to 
countdown. 
vii. Collect at least three good tests 
c. Administer 2 puffs albuterol via metered dose inhaler 
d. Repeat test using post bronchodilator fields 


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5.3.4.6 Measurement of Exhaled Nitric Oxide using NIOX Mino 
 
1. Run Test 
a. Empty Lungs 
b. Inhale deeply through the disposable filter 
c. Make a seal with mouth on mouthpiece 
d. Exhale through the disposable filter for ten seconds or longer when machine beeps 
e. View the results on the screen 
 
5.3.4.7 Randomization 
Randomization will use an adaptive biased coin algorithm using the software program R as 
the user interface. After CRF 4 is complete the SRC will leave the room and the second RC 
(referred to as RC2 from this point forward) will enter to perform the randomization process. 
 
RC2 will enter the room with the IMPROVE research cart and open the study laptop. RC2 
will open R and load the randomization algorithm program. The program will prompt RC2 to 
enter a) whether or not the patient takes hydroxyurea and b) how many ED visits or hospital 
admissions for pain the patient has had over the preceeding year c) the patients unique 
study identification number. The randomization algorithm will then notify RC2 which 
treatment arm the patient has been assigned to using a letter code (treatment arm A or B). 
Labeled study packets will be kept in the research cart and RC2 will hand the participant an 
appropriately labeled packet. At this time RC2 and the participant will open the packet 
together to review the study materials. The steps will be as follows: 
 
1. Inhaler training – RC2 will train the participant in proper use of the inhaled medication 
including inhalation technique dosing intervals, what to do about missed doses. 
2. Pain diary training – RC2 will train the participant regarding proper use of the pain 
diaries. 
3. Contact information – RC2 will instruct the participant about how to contact study 
personnel in the event that the participant loses medication, has questions, suffers 
adverse events. 
 
Once the training is complete, the participant will be instructed to put away their medication 
so that other study personnel do not see it. RC2 will leave the room. 
 
The SRC will then enter the room and explain the schedule of financial incentives. The 
participant will be given a $30 gift card and a $11 metro card. A second follow up visit will 
be scheduled for 8 weeks from the current date. At this point the participant will be released 
and any other medical care will resume. 
6.1 
Telephone follow up (week 2) 
6.2 Overview 
 
A follow up telephone call will be conducted 2 weeks after the patient is enrolled in the study. The 
goal of this phone call is to identify adverse events, to assess medication adherence, and 
pregnancy surveillance in female patients. Patients who become pregnant during the study will be 
asked to stop taking the medication and they will be withdrawn from the study. The phone script 
and event questionnaire (to assess for adverse events) is contained in CRF 2 – Adverse Events 
Form. 
 
7.1 
Telephone follow up (week 4) 
7.2 Overview 


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A follow up telephone call will be conducted 4 weeks after the patient is enrolled in the study. The 
goal of this phone call is to identify adverse events, to assess medication adherence, and 
pregnancy surveillance in female patients. Patients who become pregnant during the study will be 
asked to stop taking the medication and they will be withdrawn from the study. The phone script 
and event questionnaire (to assess for adverse events) is contained in CRF 2 – Adverse Events 
Form. 
 
8.1 
In-person follow up (week 8) 
8.2 Overview 
 
The participant will be scheduled to return for an in-person follow up 8 weeks after study initiation.  
It is likely that the participant will also need to visit the clinic for standard care. If no visit is 
indicated, the visit will be conducted for purely research purposes without billing for medical care or 
utilization of any institutional services. 
 
8.3 Intake 
 
The participant will be greeted by the SRC when they arrive at the clinic. Prior to phlebotomy the 
participant will be taken to a private area for data collection. 
 
8.4 Medication Refills 
 
If the participant meets criteria to remain in the study (see 7.2) RC2 will refill the participant’s 
medication. RC2 will go over with the patient inhaler technique and dosing schedule to confirm that 
the participant is using the medication properly. Once medication has been given to the participant, 
they will be instructed to put their medication away. 
 
8.5 Adherence Status Check 
 
CRF 8 – 8 Week Adherence Status check identifies if the participant has remained adherent to 
study guidelines (at least 70% of doses and 15 pain diaries). CRF 8 – 8 Week Adherence Status 
will be filled out by RC2 as this requires that the RC visualize study medication in an unblinded 
fashion. If at any time the participant falls below the cut-off for medication or diaries, they will be 
re-instructed to bring them back to compliance. 
 
8.6 Data collection 
8.6.1 Questionnaire 
 
The 8-week questionnaire will include data regarding respiratory symptoms, medication 
adherence, health-related quality of life, adverse events, side effects, and pregnancy 
surveillance in female patients. Patients who become pregnant during the study will be 
asked to stop taking the medication and they will be withdrawn from the study. Once it is 
confirmed by RC2 that the participant will remain in the study, CRF 5 – 8 Week Data 
Collection will be administered by the SRC. 
 
8.6.2 Serum collection 
 
Serum collection will follow the same processing procedures as 5.2.4.4. When participants 
in clinic are having blood drawn as part of standard care, research tubes will be given to the 
phlebotomist to be drawn in addition to clinical labs. 
 
8.6.3 Pulmonary function testing 


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Pulmonary function testing will be done according to the same procedure as 5.2.4.5. Data 
will be recorded in CRF 5a – Spirometry and Exhaled NO2. 
 
8.6.4 Exhaled Nitric Oxide 
 
Exhaled nitric oxide will be measured according to the same procedure as 5.2.4.6. Results 
will be recorded in CRF 5a – Spirometry and Exhaled NO2. 
 
8.7 Pain Diary Processing 
 
Completed pain diaries will be reviewed for missing data and accuracy (missing dates, ID number) 
and then brought to the SCC storage facility for processing. Complete pain diary entries are 
constituted by completion of questions 3 and 4.  Diary entries with missing answers to question 3 
and 4 will be considered incomplete. Diaries will be stored securely with other CRF’s. 
 
8.8 Financial Incentives/additional pain diaries 
 
Once data collection is complete, the SRC will give the participant a second packet of pain diaries 
to complete over the subsequent 8 weeks. The SRC will also give the patient their financial 
incentives based on the number of diaries properly filled out as indicated by the schedule below 
(table 1). 
 
 
 
 
rvation† 
ek 20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.9 Discharge and follow up arrangements 
 
After completion of data collection, a follow up visit will be scheduled for 8 weeks from the current 
date (16 weeks after study initiation). At this point the participant will be released and any other 
medical care will resume. 
 
 
9.1 
Telephone follow up (week 12) 
 
Table 1 
Timeline of financial incentives 
Visit 1 – 
Baseline 
W
Week 0 
Visit 2 
Vis 
eek 8 
W
it 3- end
Obs
e 
Participants expected 
56 
50 
45 
45 
Gift Card ($30) - 
X 
X 
X 
X 
Metro card ($11) – travel 
costs 
X 
X 
X 
X 
Gift card for completion of 
pain diaries 
< 15 diaries – 0$ 
< 15 dia
15-25 – 10$ (50%) 
15-25 – 
26-50 – 20$ (40%) 
26-50 – 
51-56 – 30$ (10%) 
51-56 – 
ries – 0$ 
< 15 diar
30$ (50%) 
15-25 – 1
60$ (40%) 
26-28 – 2
90$ (10%) 
ies – 0$ 
$ (80%) 
$ (10%) 
†Observational follow up period will continue for 4 weeks after study completion to measure adverse events, 
changes in pain and the proportion who choose to continue ICS. 


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9.2 Overview 
 
A follow up telephone call will be conducted 12 weeks after the patient is enrolled in the study. The 
goal of this phone call is to identify adverse events,to assess medication adherence, and 
pregnancy surveillance in female patients. Patients who become pregnant during the study will be 
asked to stop taking the medication and they will be withdrawn from the study. The phone script 
and event questionnaire (to assess for adverse events) is contained in CRF 2 – Adverse Events. 
 
10.0 
End of study visit (week 16) 
10.1 Overview 
 
The participant will return for a second in-person visit 16 weeks after study initiation. During this 
visit, medication administration for the purposes of research will be stopped. If the patient believes 
that the medication is helping them, then the medication may be continued if the patient’s primary 
doctor agrees to this course of care. The primary doctor will be responsible for writing prescriptions 
for inhaled steroids or for arranging subspecialty follow up with a pulmonologist. 
 
10.2 Intake 
 
The participant will be greeted by the SRC when they arrive at the clinic. Prior to phlebotomy the 
participant will be taken to a private area for data collection. 
 
10.3 Collection of study medication 
 
RC2 will collect the participants study medication once they are brought to a private area. CRF 9 – 
16 Adherence Status will be filled out by RC2 to document medication adherence.  If at any time 
the participant falls below the cut-off for medication or diaries, they will be re-instructed to bring 
them back to compliance. 
 
10.4 Procedures for individuals who wish to continue study medication 
 
If a participant expresses a desire to continue the study medication long term, the first step will be 
to determine whether the participant received placebo or drug. RC2 will reveal which treatment arm 
the participant was in. Patients who received placebo will be informed that they were not given 
medication and that there is no indication to initiate inhaled steroids at this point. For patients who 
received mometasone, the PI will contact the participant’s treating physician to discuss the case. 
Initiating long term inhaled corticosteroids will be at the treating physician’s discretion. 
 
10.5 Data collection 
 
The 16-week questionnaire will include data regarding respiratory symptoms, medication 
adherence, health-related quality of life, adverse events, side effects, and pregnancy surveillance 
in female patients. Patients who become pregnant during the study will be asked to stop taking the 
medication and they will be withdrawn from the study. Once it is confirmed by RC2 that the 
participant will remain in the study, CRF 6 – End of Study Questionnaire will be administered by 
the SRC. 
 
 
 
10.6 Pain Diary Processing 


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Completed pain diaries will be reviewed for missing data and accuracy (missing dates, ID number) 
and then brought to the SCC storage facility for processing. Diaries will be stored securely with 
other CRF’s. 
 
10.7 Financial Incentives/additional pain diaries 
 
Once data collection is complete, the SRC will give the participant a new packet of pain diaries to 
complete over the subsequent 4 weeks. The SRC will also give the patient their financial incentives 
based on the number of diaries properly filled out as indicated by table 1. 
 
10.8 Discharge and follow up arrangements 
 
After completion of data collection, a follow up visit will be scheduled for 4 weeks from the current 
date (20 weeks after study initiation). At this point the participant will be released and any other 
medical care will resume. 
 
11.0 
Post-protocol observation period visit (week 20) 
11.1 Overview 
 
The participant will return for a final, post-protocol visit 4 weeks after completion of the study. The 
goal of this visit will be to assess for adverse events in individuals who discontinued inhaled 
corticosteroids. Participants who noted substantial worsening of symptoms (SCD or breathing 
related) will be given the opportunity to have research staff speak with their primary treating 
physician regarding initiation of long term use of inhaled steroids. The primary doctor will be 
responsible for writing prescriptions for inhaled steroids or for arranging subspecialty follow up with 
a pulmonologist. 
 
11.2 Intake 
 
The participant will be greeted by the SRC when they arrive at the clinic. Prior to phlebotomy the 
participant will be taken to a private area for data collection. 
 
11.3 Procedures for individuals who wish to continue study medication 
 
If a participant expresses a desire to continue the study medication long term, the first step will be 
to determine whether the participant received placebo or drug. RC2 will reveal which treatment arm 
the participant was in. Patients who received placebo will be informed that they were not given 
medication and that there is no indication to initiate inhaled steroids at this point. For patients who 
received mometasone, the PI will contact the participant’s treating physician to discuss the case. 
Initiating long term inhaled corticosteroids will be at the treating physician’s discretion. 
 
11.4 Data collection 
 
The 20-week questionnaire will include data regarding respiratory symptoms, pain and stiffness 
modules of health-related quality of life,adverse events, and pregnancy surveillance in female 
patients. Patients who become pregnant during the study will be asked to stop taking the 
medication and they will be withdrawn from the study. The questionnaire will also ask for updated 
contact information for the participant. CRF 7 – Post Protocol Questionnaire will be administered 
by the SRC or RC2. 
 
11.5 Pain Diary Processing 


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Completed pain diaries will be reviewed for missing data and accuracy (missing dates, ID number) 
and then brought to the SCC storage facility for processing. Diaries will be stored securely with 
other CRF’s. 
 
 
 
11.6 Financial Incentives 
 
Once data collection is complete, the SRC will give the patient their financial incentives based on 
the number of diaries properly filled out as indicated by table 1. 
 
11.7 Discharge and follow up arrangements 
 
After completion of data collection, the participant will be informed that their participation in the 
study is complete. At this point the participant will be released and any other medical care will 
resume. 
 
12.0 
Procedures for loss of study medication 
 
Participants will be given contact information for the SRC and Dr. Glassberg at entry into the study. 
 
In the event that a participant loses their study medication they will be instructed to contact the SRC. 
Loss of study medication may also be identified at follow up phone calls. In this event, the SRC will 
instruct RC2 to determine which treatment arm the participant is in, obtain an additional inhaler and 
arrange to give the participant a replacement inhaler. RC2 will record on CRF 11 the date of 
replacement, and the estimated number of doses used before the initial inhaler was lost. 
 
13.1 
Data management procedures 
13.2 Study logs 
 
All study logs are maintained by the SRC with regular monitoring by the PI. 
 
13.3 Case report forms 
 
All CRF’s are maintained by the SRC with regular monitoring by the PI. Any changes to CRFs will 
require a modification of the IRB protocol. 
 
14.1 
Data Analyses 
14.2 Primary and Secondary Outcomes: The primary outcome for the study is feasibility. Feasibility will 
be determined by calculating the proportion of randomized patients who complete follow up and a 
minimum of 30 pain diaries (as was required in the PiSCES study)73 with good adherence to the 
study medication vs. the number enrolled. Other findings relevant to feasibility will include retention 
rate (% who complete the study), points of attrition, recruitment rates (# approached vs. # enrolled) 
and adherence (via dosage counters - use of more than 70% of doses) as a function of recruitment 
site (clinic vs. ED). 
14.3 Potential outcomes for a definitive multi-center trial. We will collect outcome data which will yield 
imprecise estimates of effect on patient-oriented vaso-occlusive, respiratory and safety outcomes. 
Vaso-occlusion will be measured in 5 ways 1) daily pain diaries (see exploration of potential 
definitive outcomes), 2) ED visits for pain; 3) hospital admissions (or observation unit stays) for 
pain 4) hospital admissions for ACS and 5) Health-related quality of life (change in ASCQ-Me 
score). While a primary clinical outcome was not specified, sample size calculation were based on 
detecting a difference in pain diary data (see data analysis). Respiratory outcomes will include self- 
reports of symptoms from the SAC survey. Safety outcomes include infections, adverse reactions, 
pain, avascular necrosis, stroke and intracranial hemorrhage. Data Collection and management for 


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aim 1: Data will be collected by the PI or RC in the manner described in ‘subject identification and 
recruitment’ above. All ED screening forms (CRF 1) will be kept in a file in a locked cabinet in the 
 
 
PI’s office. Relevant laboratory data will be extracted from the medical record onto case report 
forms (see CRFs). Data will then be manually entered into database REDCap database. 
Hardcopies will be maintained in a locked file cabinet in the PI’s office. Identifiable data will be kept 
in either the REDCap database or on harcopy locked in a file cabinet in the PI’s office. Hardcopy 
with identifiable data will never leave the PI’s office. All data that is shared outside of the PI’s office 
(i.e with statistician) will be stripped of identifiers and participants will be identified only by a unique 
ID number. 
14.4 Aim 2: Primary and Secondary Outcomes: This aim will assess changes in pulmonary 
inflammation and vascular injury with ICS therapy. The primary outcomes for the trial will be 
change in eNO (pulmonary inflammation) and sVCAM (vascular injury) level 8 weeks after 
randomization. Secondary outcomes will be change in reticulocyte index, change in FEV1/FVC 
ratio (expressed as percent predicted) and change in other key biomarkers. 
14.5 Data Analysis: Preliminary analyses - Descriptive analyses for all socio-demographic and clinical 
variables will be performed. Preliminary data analyses will focus on examination of the 
distributional characteristics of measures used in the study. In this step, decisions will be made 
regarding possible transformations that might be required to meet the assumptions of the statistical 
tests that will be employed. Baseline values for individuals in each randomization assignment will 
be compared using t-tests, chi-square and non-parametric tests when appropriate. For outcomes 
that may be used in a definitive trial, univariate analyses will be performed first followed by stratified 
analyses with potential confounders (variables known or suspected to have associations with the 
frequency of painful episodes including age, gender, genotype, baseline hemoglobin, leukocyte 
count, and fetal hemoglobin percent). Potential confounders with p-value less than 0.2 will be 
included in parsimonious models. 
14.6 Primary analyses: The primary outcome, feasibility as well as retention/recruitment rates, attrition 
points and adherence will be expressed for those enrolled from the ED and the hematology clinic. 
Feasibility measures will be compared between those enrolled in the ED vs. clinic using χ2 
statistics. Adherence (defined as use of greater than 70% of indicated doses by dosage counter) 
will be compared to the previously validated MARS-A score cutoff of 4.5 with a χ2 statistic to 
validate the use of MARS-A in SCD. 
14.7 Exploration of potential definitive outcomes: For the pain diary self-report measures of pain a 
linear mixed repeated measures model will be implemented with the SAS procedure MIXED to 
compare mometasone and placebo. The nesting variable will be participant ID number; main 
effects will be time, treatment group and interaction of time by treatment group. This will allow for 
variability in the number of diaries completed and variable effects of ICS over time (expected to 
increase with duration of treatment). For the measures of vaso-occlusion with poisson distributions 
(frequency of hospital visits for pain, ED visits for pain and hospital visits for acute chest 
syndrome), multivariable negative binomial regressions will be performed to estimate rate ratios 
based on treatment assignment. We expect self-report HRQL measures (change in ASCQ-Me 
score) to be approximately normally distributed. Pain diary data will be expressed in terms of 
several summary measures as described I the PiSCES project including number of days in ‘crisis’, 
number of pain days, number of days requiring opiate use and mean pain severity.71 Categorical 
summary measures will be compared with χ2 statistic, continuous variables will be compared with 
t-tests or non-parametric tests as appropriate. Additionally, for potential patient-oriented outcomes, 
a series of Bayesian analyses will be performed. For normally distributed variables (i.e. ASCQ-Me 
pain domains) a posterior distribution will be estimated for the difference between treatment 
groups. This will be achieved by using a non-informative Gaussian distribution as the conjugate 
prior. Markov-chain monte carlo simulation will be used to obtain random samples from the 
posterior distributions of each treatment group such that the distribution of the difference between 
treatments can be estimated. The same procedure will be used for other patient-oriented 
outcomes. For poisson distributed outcomes (ED visits, hospital admissions) a gamma prior will be 


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used, for binomial outcomes we will use a beta prior. All Bayesian analyses will be performed in R. 
 
 
Bayesian analyses will also be used to estimate adverse events if any occur. 
14.8 Sample Size Analysis: While the primary outcome of the study is feasibility, we did perform a 
sample size analysis to estimate measures of treatment effectiveness based on mean pain scores 
from pain diaries. It is unlikely that average correlation before and after treatment would be equal  
to 0.5 because we expect the treatment group's pain scores to decline while the control group 
remains about the same. For the proposed sample sizes, to detect a difference in mean pain score 
of 1 point for ICS vs placebo if the correlation is 0.40, power = 0.74, for a correlation of 0.30, power 
= 0.77, and for 0.20, power = 0.80.84 
14.9 Data Analysis: Preliminary analyses will be performed as described in Aim 1. For the primary 
outcome eNO and sVCAM 
170,251.61 
-175,849.40 
14.10 
, change scores will be created by subtracting levels drawn at 8 weeks from those drawn at 
study entry. These change scores will be analyzed using a t-test with treatment group as the 
explanatory variable. Change scores and t-tests will be calculated for the secondary outcomes 
(sVCAM, reticulocyte index, FEV1/FVC, other biomarkers) in the same manner. Additional 
Bayesian analyses will also be performed to estimate changes in biomarkers using the same 
techniques described in “exploration of potential definitive outcomes” above. 
14.11 
Sample Size Analysis: Using a correlation of 0.5 between pre and post-treatment eNO 
levels, the proposed sample size will have 80% power to detect a difference of 5 ppb between 
mometasone and placebo. The study will have 90% power to detect a difference of 5.8 ppb.101 
Thus we will have adequate power to detect even small reductions in levels of eNO across 
treatments. 
14.12 
Interim Data Analysis: Interim data analysis will be done after the first 20 participants 
have been enrolled. Interim analysis will use the same analytical analyses above. 
 
15.1 
Schedule of oversight procedures 
15.2 DSMB meetings 
 
In accordance with NIH policy, a Data Safety Monitoring Board (DSMB) will be constituted. The 
DSMB will consist of members of the advisory committee: Dr. Strunk, Dr. Wisnivesky, and Dr. 
DiMaggio. The DSMB will report Adverse Events (AEs) to the Mount Sinai Institutional Review 
Board, the funding I/C, the NIH Office of Biotechnology Activities (OBA), and the Food and Drug 
Administration (FDA) in accordance with Investigational New Drug (IND) regulations. The DSMB  
will meet prior to subject enrollment and data collection and will meet at 6 month intervals thereafter 
to review study progress and monitor patient safety. The responsibilities of the DSMB will include: 
1) overseeing the study’s progress, 2) approving alterations or amendments to the study protocol, 
3) monitoring safety and reviewing serious adverse events (SAE), 4) overseeing data quality, 5) 
reviewing the interim analyses and recommending early trial cessation if indicated. The PI will be 
responsible for providing the DSMB with all necessary information. 
 
As per IRB policies, all SAEs regardless of relationship to the research will be reported to the IRB 
within 24 hours and will be listed in the annual IRB application for continuation or termination of the 
research. All expected non-serious adverse events that occur at a greater frequency or severity 
than anticipated and all unexpected non-serious adverse events will be reported to the IRB within 
15 working days and summarized annually to the IRB in the continuation or termination 
applications. Reports of adverse events will also be reviewed by the PI and the primary mentor at 
their weekly meeting. Questions and concerns will be discussed with the DSMB during scheduled 
meetings or in between meetings if a more serious concern arises. 
 
15.3 FDA annual reports 


21 
Inhaled Mometasone to Promote Reduction Of Vaso-occlusive Events 
Rev 11-18-15 
Manual of Operating Procedures 
 
 
 
The IND for this study is held by Dr. Glassberg. Dr. Glassberg is responsible for maintaining 
compliance with FDCA (21 U.S.C. §§ 301 et. Seq.) as well as implementing regulations [title 21 of 
the code of federal regulations (CFR)]. All reporting requirements described in the IND will be med. 
 
16.0 
Provisions for research related injury 
 
The physicians on the research team and the DSMB will address any adverse events or refer the study 
participants for specialized treatment, if appropriate. Adverse events will be recorded in CRF 2 and 
deaths will be recorded on CRF 12. Published data suggest that inhaled mometasone at this dose will 
not cause serious adverse events in this population. If a study participant develops an adverse event, 
decisions will be made on a case-by-case basis to determine if the patient should be withdrawn from 
the study. 
As discussed above, there are risks associated with participation in the proposed project. As detailed in 
HRP 503, risks associated with participation are minimal and all efforts will be made to avoid these 
risks. Staff will be trained to minimize risks associated with phlebotomy and other collection procedures. 
With regard to the risks associated with inhaled mometasone, the risks of adverse events are extremely 
low with the proposed dose of study medication. Participants will be followed very closely to assess for 
adverse events (see Data Safety and Monitoring Plan). For individuals who benefit from ICS, all efforts 
will be made to make ICS available via prescriptions from the participant’s primary provider after 
conclusion of the study. Individuals randomized to placebo will be contacted after study data are 
analyzed to inform them if ICS are beneficial. The PI will also offer to contact primary providers for 
patients randomized to placebo if they would like to begin treatment with ICS. 
If at any time, a subject expresses verbal or nonverbal unwillingness to participate, the subject will be 
withdrawn from the study. 
 
17.0 
Procedures for study withdrawal 
 
Any participant experiencing serious adverse events will be considered for exclusion after adjudication 
by the DSMB. 


22 
Inhaled Mometasone to Promote Reduction Of Vaso-occlusive Events 
Rev 11-18-15 
Manual of Operating Procedures 
 
 
 
18.1 Appendices 
 
 
 
 
 
18.1 
 
 
 
 
 
Appendix 3 – 
HIMC SOPs 


 
Supplement 2: Screening and eligibility form 


CRF 3 – Screening Questionnaire 
Revision Date: 07/07/14 
 
 
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Inhaled 
Mometasone to 
Promote Reduction 
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Screening questionnaire to determine eligibility 
 
 
 
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CRF 3 – Screening Questionnaire 
Revision Date: 07/07/14 
 
 
 
 
 
 
 
Inclusion/Exclusion Scheme: 
Participants are eligible if they do not answer ‘never’ to all questions in group 4 
 
Exclude Participants if 
a. 
They answer yes to all 3 questions in group 1 
b. 
They answer yes to 2 questions in group 1 and 1 or more questions in group 2 
c. 
They answer yes to questions 6 and 7 or questions 6 and 8 
d. 
They answer yes to questions 12 , 14, 15  and >15 for question 13 in group 5 
 
Investigator Approval of Eligibility: 
_ Date:   
 
GROUP 5 
12. Is the patient currently experiencing a sickle cell pain crisis? 
Yes 
No 
13. Over the past 12 months how many ED or hospital visits did you have for sickle cell pain? 
0-5 
6-10 
11-15 
>15 (EXCLUDE) 
14. Have you been admitted or discharged from the hospital in the past 7 days? 
Yes 
No 
15. FEMALE PATIENTS ONLY: Is the patient Pregnant? 
Yes 
No 
Group 4 
9. During the past 2 months, how often did the participant awaken from sleep because of cough or 
wheeze? 
Never 
Almost every night 
At least once a week but not nightly 
At least once a month but not weekly 
At least once but not monthly 
10. During the past 2 months, how often did the participant cough or wheeze during or after exercise? 
Never 
Almost every night 
At least once a week but not nightly 
At least once a month but not weekly 
At least once but not monthly 
11. During the past 2 months, how often did the participant cough or wheeze during the day unrelated to 
exercise? 
Never 
Almost every night 
At least once a week but not nightly 
At least once a month but not weekly 
At least once but not monthly 


Supplement 3: Inhaler training and adherence modules 
 
 


 
 
(Affix Label Here) 
Participant ID:    
Date Form Filled Out: 
day 
month 
year 
Inhaled 
Mometasone to 
Promote Reduction 
of Vaso-occlusive 
Events 
 
Protocol Orientation Module A 
 
If you lose your medication 
 
Contact study staff immediately: 
 
 
  
 
 
 
Pain diaries 
 
Pain diaries are included in your package. Try to fill out a pain diary every 
day. If you miss a day that’s ok. You must fill out at least 30 diaries to stay 
in the study. 
Your medicine 
 
This package contains your medicine for this study. Take one puff of the 
medicine every day. The research coordinator will teach you how to use 
the inhaler. 


 
 
(Affix Label Here) 
Participant ID:    
Date Form Filled Out: 
  
  
__   
  
  
  
day 
month 
year 
Inhaled 
Mometasone to 
Promote Reduction 
of Vaso-occlusive 
Events 
 
Protocol Orientation Module: Adapted from “BREATHE EASIER: AN 
ADULT ASTHMA EDUCATION PROGRAM” and Mometasone 
Package Insert 
“Breathe Easier” 
Developed by the American Institutes for Research and 
the Kaiser-Permanente Medical Group 
National Heart, Lung, and Blood Institute 
National Institutes of Health 
National Asthma Education and Prevention Program 
 
 
 
 
 
FOR ORAL INHALATION ONLY 
 
 
Please read this leaflet carefully before taking this medication 
This leaflet does not contain the complete information about this medication. If you have any questions about mometasone inhalation ask your health care provider or 
pharmacist. 
 
IMPORTANT POINTS TO REMEMBER 
 
• 
Use this medication regularly and at the same time each day, as prescribed by your health care provider. You or your child may not get the most benefit for 1 to 2 
weeks or longer after starting the medication. If you or your child’s symptoms do not improve in that time frame or if your condition gets worse, contact your health 
care provider. 
 
• 
The cap is needed to use the TWISTHALER. Do not twist the mouthpiece with your hand. When the cap is removed from the TWISTHALER, the dose counter will 
count down by one, and show the number of doses available after this use. 
 
• 
The inhaler delivers your medicine as a very fine powder that you or your child may not taste, smell, or feel. Do not take or give extra doses unless your health care 
provider has told you to. 
 
• 
It is important to replace the cap after each inhalation to protect the inhaler from moisture. 
 
• 
Do not use the inhaler if you notice that it is not working correctly. Take it to your health care provider or pharmacist. 


 
UNDERSTANDING YOUR MEDICATIONS 
MATERIALS FOR SESSION: 
• twisthalers 
 
As part of this study you will be given an inhaler. This inhaler may contain placebo (no 
medication) or it may contain a medicine called mometasone. Mometasone is part of a class 
of medications called corticosteroids. 
 
This is a medication taken regularly every day even when you don't have any symptoms 
 
Although they have a similar name, these steroids are very different from the anabolic 
steroids that have been in the news in recent years because of their ill-advised use by athletes 
to increase muscle mass. 
 
 
Corticosteroids are: 
• Anti-inflammatory-Corticosteroids are a very effective anti-inflammatory medication and 
help reduce or prevent edema and excess mucus in the bronchial tubes. 
• Have delayed action-· Corticosteroids do not relax the muscles around the bronchial tubes 
and will not open the airways immediately as do the bronchodilators. For this reason, they 
may not seem to have any effects. However, over time they can be very beneficial in 
reducing inflammation. 
 
Inhaled corticosteroids have very few side effects, when used in moderate doses, but they 
must be taken regularly to be effective. 
 
Possible side effects: an unpleasant taste and gastrointestinal symptoms (e.g., nausea). They 
may cause a yeast infection (“thrush”) in the mouth or bother the upper airways and cause 
coughing. 
 
Proper Inhaler Use (10 minutes) 
The medication that we have been discussing is administered by aerosol inhaler, and proper 
inhaler use is very important for maximum benefit. If inhalers are not used correctly, the 
medications don't help much because they can't get all the way down into the narrow 
airways. Many times patients stop using their inhalers (or, on the other hand, overuse their 
inhalers) because they think the medicine is not working. In reality, it's not working only 
because they aren't using it right. 
 
Go over steps while you demonstrate correct usage. 
 
 
Instruct participants to take one puff per day 
 
Let's take a few minutes to review inhaler use and make sure each of you is using the best 
technique. 


 
How To Use YOUR INHALER 
 
 
HOW TO USE ASMANEX TWISTHALER OR GIVE TO YOUR CHILD 
 
• 
Remove the ASMANEX TWISTHALER from its foil pouch and write the date on the cap label. 
• 
Throw away the inhaler 45 days after this date or when the dose counter reads “00”, indicating the final dose has been inhaled, whichever comes 
first. 
• 
Follow steps 1 and 2 below each time you inhale a dose from your ASMANEX TWISTHALER. 
Inhaler Parts: 
See Figures 1 and 2 below to become familiar with the inhaler parts. 
 
 
 
 
 
 
 
 
 
Figure 1: Inhaler (upright position) 
Figure 2: Inhaler with Cap Removed 
Step 1: Open inhaler 
Hold the inhaler straight up (upright position) with the colored portion (the base) on the bottom (see Figure 3 below). It is important that you remove the cap of the 
TWISTHALER while it is in this upright position to make sure that you get the right amount of medicine with each dose. 
 
Holding the colored base, twist the cap in a counterclockwise direction to remove it (see Figure 3 below). As you lift off the cap, the dose counter on the base will count 
down by one. Removing the cap loads the TWISTHALER with the medicine that you are now ready to inhale. 
 
 
Figure 3: Cap Removal Loads Dose 
 
 
IT IS IMPORTANT TO NOTE that the indented arrow (located on the white portion of the TWISTHALER, directly above the colored base) is pointing to the dose 
counter (see Figure 2). 


 
Step 2: Inhale dose 
Breathe out fully. Then bring the TWISTHALER up to your mouth or your child’s mouth with the mouthpiece facing toward you or your child. Place the mouthpiece in 
your mouth or your child’s mouth, holding it in a horizontal (on its side) position as shown below (see Figure 4). Firmly close your lips around the mouthpiece and take 
in a fast, deep breath. Since the medicine is a very fine powder, you may not be able to taste, smell, or feel it after inhalation. Do not cover the ventilation holes while 
inhaling the dose. 
 
 
Figure 4: Inhalation 
 
Remove the TWISTHALER from your mouth and hold your breath for about 10 seconds, or as long as you comfortably can. 
 
IMPORTANT: DO NOT BREATHE OUT (EXHALE) INTO THE INHALER. 
 
After you take your medicine, it is important that you wipe the mouthpiece dry, if needed, and then REPLACE THE CAP, firmly closing the TWISTHALER right 
away (see Figures 5 and 6 below). 
 
Be sure that the indented arrow is in line with the dose counter. Put the cap back onto the inhaler and turn it in a clockwise direction, as you gently press down. You’ll 
hear a “click” to let you know that the cap is fully closed. This is the only way to be sure that your next dose is loaded the right way. 
 
 
 
Figure 5: Closing the Inhaler 


 
 
 
Figure 6: Closed Inhaler 
 
 
IT IS IMPORTANT TO REPEAT STEPS 1 AND 2 EACH TIME YOU INHALE. 
 
Rinse your mouth after using. 
 
STORING YOUR INHALER 
 
• 
Keep your inhaler clean and dry at all times. If the mouthpiece needs cleaning, gently wipe the mouthpiece with a dry cloth or tissue as needed. Do not 
wash the inhaler. Avoid contact with any liquids. 
 
• 
Store in a dry place at 25°C (77°F) [may range between 15-30°C (59-86°F)]. 
 
• 
Keep your inhaler out of the reach of children. 
 
HOW TO KNOW WHEN YOUR INHALER IS EMPTY 
The inhaler has a dose counter on the colored base, which shows the number of doses left to use. As you lift off the cap to take your dose, the dose counter on the base 
will count down by one (if you began with the dose counter reading “30” this will cause the dose counter to now read “29”). Read the numbers from top to bottom. 
 
When the unit reads “01” this indicates the last remaining dose. After dose “01” the counter will read “00”. When you replace the cap, the unit will lock and then must 
be thrown away. Start using a new ASMANEX TWISTHALER as instructed by your health care provider. 


 
Practical Solutions to Problems Using an Inhaler (10 minutes) 
Sticking to a schedule for using an inhaler can be pretty demanding, especially if you take other 
medications or take them several times a day. If your schedule for medications is very 
complicated, you may want to discuss with your physician and see if a simpler schedule can be 
worked out. Sometimes people do all right during the week but have problems keeping on 
schedule on the weekend or on vacation or traveling because they're not following their 
regular routine. Handout 14 describes some practical solutions to problems like forgetting 
your medication, coping with unpleasant side effects, or being embarrassed when you 
have to use your inhaler in a public place. Let's take a minute to read over the handout and 
then talk about which of these solutions seems personally useful to each of you. You might 
also have some suggestions that aren't on the handout. 
 
Practical Solutions to Problems Using an Inhaler 
With particular reference to finding specific solutions for class members. Elicit participants' 
feelings about taking medications on a routine basis. 
 
Overuse of Medications ( 10 minutes) 
Medication underuse includes things like: 
• Skipping doses 
• Being careless about the timing of your doses 
• Discontinuing routine medications altogether 
The opposite side of the coin is medication overuse. Surprisingly, the two problems can 
often go together. When you skip your medications you may be tempted to double up 
to bring things back under control. This is much harder on your body and may even lead to 
dangerous drug reactions. 
 
In general, there are two dangers associated with medication overuse: 
• Overused medication can cause more side effects sometimes even severe toxic reactions. 
PRACTICAL SOLUTIONS TO PROBLEMS USING AN INHALER 
There are several common problems people have trying to stick to their medication plans. Here are some 
tips and hints for overcoming them. 
Problems Solutions 
1. Use alarm clocks or watches with built-in alarm functions 
2. Take your inhaler at the same time as another regular habit, such as before or after you eat, before you 
brush your medication teeth, or when you go to bed. Keep them visible. 
3. Carry your medicines with you at all times, in your purse, briefcase, etc.; pack in carry-on luggage 
when traveling. 
4. Use a written medication schedule or keep a diary for several weeks until you begin to establish good 
medication taking habits. 
5. Check before a trip to make sure you have enough medication to last until you come back home. 


 
 
(Affix Label Here) 
Participant ID:    
Date Form Filled Out: 
day 
month 
year 
Inhaled 
Mometasone to 
Promote Reduction 
of Vaso-occlusive 
Events 
 
Protocol Orientation Module B 
 
If you lose your medication 
 
Contact study staff immediately: 
 
 
  
 
 
 
Pain diaries 
 
Pain diaries are included in your package. Try to fill out a pain diary every 
day. If you miss a day that’s ok. You must fill out at least 30 diaries to stay 
in the study. 
Your medicine 
 
This package contains your medicine for this study. Take one puff of the 
medicine every day. The research coordinator will teach you how to use 
the inhaler. 


 
 
(Affix Label Here) 
Participant ID:    
Date Form Filled Out: 
  
  
__   
  
  
  
day 
month 
year 
Inhaled 
Mometasone to 
Promote Reduction 
of Vaso-occlusive 
Events 
 
Protocol Orientation Module: Adapted from “BREATHE EASIER: AN 
ADULT ASTHMA EDUCATION PROGRAM” and Mometasone 
Package Insert 
“Breathe Easier” 
Developed by the American Institutes for Research and 
the Kaiser-Permanente Medical Group 
National Heart, Lung, and Blood Institute 
National Institutes of Health 
National Asthma Education and Prevention Program 
 
 
 
(mometasone furoate inhalation) 
FOR ORAL INHALATION ONLY 
Please read this leaflet carefully before taking your medication. 
This leaflet does not contain the complete information about this medication. If you have any questions about this medicine, ask your health care 
provider or pharmacist. 
 
IMPORTANT POINTS TO REMEMBER 
 
• 
Use your inhaler regularly and at the same time each day, as prescribed by your health care provider. You or your child may not get the most benefit for 1 to 2 weeks or 
longer after starting the medication. If you or your child’s symptoms do not improve in that time frame or if your condition gets worse, contact your health care provider. 
 
• 
The inhaler delivers medicine that you or your child may not taste, smell, or feel. Do not take or give extra doses unless your health care provider has told you to. 
 
• 
It is important to replace the cap after each inhalation to protect the inhaler from moisture. 
 
• 
Do not use the inhaler if you notice that it is not working correctly. Take it to your health care provider or pharmacist. 


 
UNDERSTANDING YOUR MEDICATIONS 
MATERIALS FOR SESSION: 
• MHWHUHG GRVH LQKDOHUV 
 
As part of this study you will be given an inhaler. This inhaler may contain placebo (no 
medication) or it may contain a medicine called mometasone. Mometasone is part of a class 
of medications called corticosteroids. 
 
This is a medication taken regularly every day even when you don't have any symptoms 
 
Although they have a similar name, these steroids are very different from the anabolic 
steroids that have been in the news in recent years because of their ill-advised use by athletes 
to increase muscle mass. 
 
 
Corticosteroids are: 
• Anti-inflammatory-Corticosteroids are a very effective anti-inflammatory medication and 
help reduce or prevent edema and excess mucus in the bronchial tubes. 
• Have delayed action-· Corticosteroids do not relax the muscles around the bronchial tubes 
and will not open the airways immediately as do the bronchodilators. For this reason, they 
may not seem to have any effects. However, over time they can be very beneficial in 
reducing inflammation. 
 
Inhaled corticosteroids have very few side effects, when used in moderate doses, but they 
must be taken regularly to be effective. 
 
Possible side effects: an unpleasant taste and gastrointestinal symptoms (e.g., nausea). They 
may cause a yeast infection (“thrush”) in the mouth or bother the upper airways and cause 
coughing. 
 
Proper Inhaler Use (10 minutes) 
The medication that we have been discussing is administered by aerosol inhaler, and proper 
inhaler use is very important for maximum benefit. If inhalers are not used correctly, the 
medications don't help much because they can't get all the way down into the narrow 
airways. Many times patients stop using their inhalers (or, on the other hand, overuse their 
inhalers) because they think the medicine is not working. In reality, it's not working only 
because they aren't using it right. 
 
Go over steps while you demonstrate correct usage. 
 
 
Instruct participants to take one puff per day 
 
Let's take a few minutes to review inhaler use and make sure each of you is using the best 
technique. 


 
How to Use Your Inhaler 
 
Get Ready 
1. Shake the inhaler well for a few seconds before using. Remove the cap. 
2. Tilt your head back slightly to straighten the airways to your lungs. 
3. Hold the inhaler with your thumb on the bottom and your index or middle finger on top (see 
picture). 
4. Breathe out fully to empty your lungs. 
5. Place inhaler 1 to 2 inches in front of your open mouth.* 
Inhale Slowly, Press Inhaler 
6. Breathe in slowly through your mouth as you press the inhaler once. Keep breathing in slowly 
without stopping for as long as you can. 
Hold Breath 
7. Hold your breath for 10 seconds. This allows the medicine to reach deeply into your lungs. 
 
 
 
 
 


 
Practical Solutions to Problems Using an Inhaler (10 minutes) 
Sticking to a schedule for using an inhaler can be pretty demanding, especially if you take other 
medications or take them several times a day. If your schedule for medications is very 
complicated, you may want to discuss with your physician and see if a simpler schedule can be 
worked out. Sometimes people do all right during the week but have problems keeping on 
schedule on the weekend or on vacation or traveling because they're not following their 
regular routine. Handout 14 describes some practical solutions to problems like forgetting 
your medication, coping with unpleasant side effects, or being embarrassed when you 
have to use your inhaler in a public place. Let's take a minute to read over the handout and 
then talk about which of these solutions seems personally useful to each of you. You might 
also have some suggestions that aren't on the handout. 
 
Practical Solutions to Problems Using an Inhaler 
With particular reference to finding specific solutions for class members. Elicit participants' 
feelings about taking medications on a routine basis. 
 
Overuse of Medications ( 10 minutes) 
Medication underuse includes things like: 
• Skipping doses 
• Being careless about the timing of your doses 
• Discontinuing routine medications altogether 
The opposite side of the coin is medication overuse. Surprisingly, the two problems can 
often go together. When you skip your medications you may be tempted to double up 
to bring things back under control. This is much harder on your body and may even lead to 
dangerous drug reactions. 
 
In general, there are two dangers associated with medication overuse: 
• Overused medication can cause more side effects sometimes even severe toxic reactions. 
PRACTICAL SOLUTIONS TO PROBLEMS USING AN INHALER 
There are several common problems people have trying to stick to their medication plans. Here are some 
tips and hints for overcoming them. 
Problems Solutions 
1. Use alarm clocks or watches with built-in alarm functions 
2. Take your inhaler at the same time as another regular habit, such as before or after you eat, before you 
brush your medication teeth, or when you go to bed. Keep them visible. 
3. Carry your medicines with you at all times, in your purse, briefcase, etc.; pack in carry-on luggage 
when traveling. 
4. Use a written medication schedule or keep a diary for several weeks until you begin to establish good 
medication taking habits. 
5. Check before a trip to make sure you have enough medication to last until you come back home. 


 
Supplement 4: Procedures for pulmonary function tests 
 
Exhaled nitric oxide (eNO) 
Online FENO measurement with the NIOX system (Aerocrine AB, Stockholm, 
Sweden) was performed according to ATS guidelines.23  FENO measurement used a 
resistive device that provided a constant low expiratory flow rate and vellum closure. 
Participants were required to exhale to residual volume; a mouthpiece was then 
inserted, and the participant was asked to inhale to total lung capacity. Thereafter, the 
participant exhaled for 10 seconds at a constant flow rate of 0.05 L/s ± 10%. If a subject 
did not manage to keep the flow or pressure within the required ranges over the 
10 seconds of exhalation, the user profile was changed to 6 seconds per ATS 
guidelines, and the test was repeated. 
 
Spirometry 
After completion of FENO measurements, spirometry was performed by specially 
trained and certified research coordinators according to ATS standards,24 as previously 
described.25Appropriate prediction equations for FEV1, FVC, and FEV1/FVC ratio were 
used, taking into account age, sex, height, and ethnicity.26 To measure bronchodilator 
response, technicians administered 2 inhalations of albuterol to participants using an 
AeroChamber. Spirometry was repeated 15 minutes after albuterol. An increase of 12% 
or greater in FEV1  after albuterol was considered a positive bronchodilator response.27
 
 
Overreading of spirometric and FENO results 
Results were reviewed by a single investigator (G.S.) to ensure ATS criteria were 
met for spirometry and FENO measurement; invalid tests were excluded from analyses. 


 
Supplement 5: Attrition 
 
Participant 
Reason for attrition 
Assignment 
Duration of participation 
1 
Moved out of state 
Drug 
4 weeks 
2 
Took one dose and dropped out of study 
Placebo 
1 week 
3 
Lost to follow up could not contact 
Drug 
8 weeks 
4 
Moved out of the country 
Drug 
7 weeks 
5 
Lost to follow up could not contact 
Placebo 
8 weeks 


 
Supplement 6: Additional Data 
 
Adjusted Intent to treat analyses 
Placebo (17) 
Drug (35) 
Treat- 
ment 
Effect 
95%CI 
P 
value 
Additional biological outcomes (pg/mL) 
Δ TNF-α 
Mean (SD) 
-0.62 (4.21) 
-1.76 (4.38) 
-1.00 
-3.74 – 1.74 
0.47 
LS mean (SE)*** 
-0.66 (1.24) 
-1.77 (0.91) 
Median (range) 
0.00 (18.37) 
-1.08 (20.21) 
Percent change (SD) 
-1.78% (8.85) 
-1.98% (11.60) 
Δ IFN-γ 
Mean (SD) 
-5.59 (13.25) 
-5.30 (17.83) 
-0.64 
-11.04 – 9.76 
0.90 
LS mean (SE)*** 
-5.76 (4.71) 
-5.45 (3.47) 
Median (range) 
-5.37 (52.57) 
-1.00 (96.64) 
Percent change (SD) 
-1.46% (13.53) 
-3.17% (13.67) 
Δ IL1β 
Mean (SD) 
-0.96 (4.13) 
-0.60 (2.01) 
0.05 
-1.75 – 1.85 
0.96 
LS mean (SE)*** 
-0.98 (0.82) 
-0.61 (0.60) 
Median (range) 
0.00 (17.45) 
-0.24 (9.26) 
Percent change (SD) 
4.44% (26.01) 
-2.32% (9.53) 
Δ IL-6 
Mean (SD) 
-1.94 (5.09) 
-1.06 (5.69) 
-0.18 
-3.52 – 3.16 
0.92 
LS mean (SE)*** 
-1.96 (1.51) 
-1.08 (1.11) 
Median (range) 
-1.00 (22.79) 
-0.59 (35.12) 
Percent change (SD) 
-5.79% (27.78) 
-1.58% (33.11) 
Δ E-selectin 
Mean (SD) 
-1899.83 
(7241.93) 
411.43 
(11556.06) 
2803.95 
-3739.43 – 
9347.33 
0.86 
LS mean (SE)*** 
-1883.40 
(2961.85) 
338.75 
(2182.35) 
Median (range) 
-415.05 
(29491.00) 
-1711.15 
(47937.91) 
Percent change (SD) 
-1.40% (19.18) 
1.09% (22.65) 
Δ P-selectin 
Mean (SD) 
90.26 
(7342.84) 
209.47 
(6622.81) 
252.04 
-4099.28 – 
4603.36 
0.91 
LS mean (SE)*** 
-3.14 
(1969.62) 
173.91 
(1451.26) 
Median (range) 
292.41 
(32713.32) 
813.13 
(32442.13) 
Percent change (SD) 
-2.29% (17.63) 
2.49% (19.17) 
Δ IL4 
Mean (SD) 
-5.58 (16.92) 
-2.20 (17.59) 
2.88 
-8.13 – 13.88 
0.60 
LS mean (SE)*** 
-5.75 (4.98) 
-2.21 (3.67) 


 
 
Median (range) 
-4.83 (61.54) 
0.32 (69.31) 
Percent change (SD) 
-2.06% (6.30) 
0.28% (9.65) 
Δ IL2 
Mean (SD) 
12.24 (53.50) 
-23.34 (47.38) 
-37.39 
-79.09 – 4.32 
0.08 
LS mean (SE)*** 
12.86 (18.91) 
-24.46 (13.62) 
Median (range) 
-2.15 (166.69) 
-18.69 (183.84) 
Percent change (SD) 
8.21% (30.77) 
-7.39% (19.66) 
Δ IL13 
Mean (SD) 
-272.22 
(759.84) 
1761.58 
(10544.69) 
2065.02 
-3428.07 – 
7558.10 
0.45 
LS mean (SE)*** 
-270.46 
(2486.48) 
1799.18 
(1832.06) 
Median (range) 
-53.25 
(3329.69) 
-45.50 
(61862.11) 
Percent change (SD) 
-4.35% (16.39) 
70.73% (418.93)