A Comparison of Individualized vs. Weight Based Protocols to Treat Vaso-Occlusive Episodes in Sickle Cell Disease
Phase: PHASE3
Conditions: Sickle Cell Disease
Sponsor: Duke University

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Study Protocol 
 
 
A Comparison of Individualized vs. Weight Based Protocols to Treat  
Vaso-Occlusive Episodes in Sickle Cell Disease  
SHORT TITLE: COMPARE VOE 
 
 
ClinicalTrials.gov Identifier:  
 
NATIONAL, HEART, LUNG AND BLOOD INSTITUTE 
NATIONAL INSTITUTES OF HEALTH 
Compiled by: 
Duke Clinical Research Institute 
Version 2.0  
 April 30, 2019 
 
 
Distributed by: 
Duke Clinical Research Institute 
Duke University 
P.O. Box 17969 
Durham, NC 27715 

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Study Funding: 
National Heart, Lung, and Blood Institute 
National Institutes of Health 
 
 
Project Officer: 
 Ellen M. Werner, Ph.D., M.A. (NHLBI) 
 
Study Chairs: 
Paula Tanabe, Ph.D, CCC PI 
 
Huiman Barnhart, Ph.D., DCC PI  
 
 
 
 
 
 
 

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PROTOCOL VERSION AND AMENDMENT TRACKING 
 
Version Number/Amendment 
Approval Date 
1.0 
01/08/2019 
            2.0 
            4/30/2019 

4 
 
TABLE OF ABBREVIATIONS 
ACS 
Acute Chest Syndrome 
ACEP 
American College of Emergency Physicians 
AE 
Adverse Event 
CCC 
Clinical Coordinating Center 
CI 
Confidence Interval 
Co-I 
Co-Investigator 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DSMB 
Data Safety Monitoring Board  
eCRF 
Electronic Case Report Form 
EC 
Executive Committee 
ED 
Emergency Department 
EDC 
Electronic Data Capture 
EMR 
Electronic Medical Record 
GCP 
Good Clinical Practices 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Counsel for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ITT 
Intent To Treat 
IV 
Intravenous 
IVMSE 
Intravenous Morphine Sulfate Equivalents 
KG 
Kilogram 
MG 
Milligram 
MoP 
Manual of Operations 
MM 
Millimeter 
NHLBI 
National Heart, Lung and Blood Institute 
NSAIDS 
Non-Steroidal Anti-Inflammatory Drugs 
PHQ 
Patient Health Questionnaire  
PI 
Principal Investigator 
RA 
Research Associate 
RCT 
Research Clinical Trial 
RR 
Respiratory Rate 

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SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SCD 
Sickle Cell Disease 
SD 
Standard Deviation  
SpO2 
Peripheral Saturation of Oxygen 
TBD 
To Be Determined 
VOC 
Vaso-Occlusive Crisis 
VOE 
Vaso-Occlusive Episode 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS
 
STUDY PROTOCOL ........................................................................................................................... 1 
PROTOCOL VERSION AND AMENDMENT TRACKING .................................................................. 3 
TABLE OF ABREVIATIONS ................................................................................................................ 4 
1. EXECUTIVE SUMMARY ................................................................................................................ 9 
2. HYPOTHESES AND OBJECTIVES ............................................................................................. 10 
2.1 Primary Objectives and Hypothesis .............................................................................................. 10 
2.2 Secondary Objectives .................................................................................................................. 10 
3. BACKGROUND AND RATIONALE .............................................................................................. 11 
4. BASIC STUDY DESIGN .............................................................................................................. 12 
5. STUDY POPULATION AND ELIGIBILITY CRITERIA ................................................................. 13 
5.1 Population for randomization ........................................................................................................ 13 
5.1.1. 
Inclusion Criteria .............................................................................................................. 13 
5.1.2. 
Exclusion Criteria ............................................................................................................. 13 
5.2  Study population with Primary and Secondary Outcomes ............................................................ 13 
5.2.1. 
Inclusion Criteria: ............................................................................................................. 14 
5.2.2. 
Exclusion Criteria ............................................................................................................. 14 
6. TREATMENT INTERVENTIONS ................................................................................................. 14 
6.2. Overview of Treatment Interventions ........................................................................................... 14 
6.3.Blinding ......................................................................................................................................... 14 
6.4.Patient Safety and Concomitant Therapies .................................................................................. 14 
7. RECRUITMENT AND SCREENING PROCEDURES .................................................................. 14 
7.2.Common Recruitment/Screening Procedures .............................................................................. 14 
7.2 Estimated Enrollment Period ........................................................................................................ 15 
8. INITIAL STUDY EVALUATIONS AND RANDOMIZATION .......................................................... 15 
8.2.Screening for Informed Consent and Patient Randomization ....................................................... 15 
8.3.Randomization and Patient Protocols ........................................................................................... 15 
Patient-Specific Protocol ........................................................................................................... 16 
Weight-Based Protocol .............................................................................................................. 17 
9. STUDY ENROLLMENT AND COMPLETION AT ED VISIT ......................................................... 18 
10. FOLLOW-UP DATA COLLECTION. ............................................................................................. 19 
11. OUTCOME DETERMINATIONS .................................................................................................. 19 
11.1. 
Primary Endpoint ............................................................................................................. 19 
11.2. 
Secondary Endpoints ...................................................................................................... 19 

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12. PARTICIPANT SAFETY AND ADVERSE EVENTS .................................................................... 19 
12.1. 
Institutional Review Boards .............................................................................................. 19 
12.2. 
Informed Consent ............................................................................................................ 19 
12.3. 
Voluntary Withdrawal from the Study .............................................................................. 20 
12.4. 
Summary of the Risks and Benefits................................................................................. 20 
12.5. 
Collection and Reporting of Adverse Events ..................... Error! Bookmark not defined. 
12.5.1 
Protocol Specific Adverse Events ................................................................................... 19 
12.6 
Collection and Reporting of Serious Adverse events ..................................................... 20 
12.6.1 
Protocol Specific serious Adverse events ...................................................................... 20 
12.7 
Expedited Reproting........................................................................................................ 21 
12.8 
Acute Chest Syndrome ................................................................................................... 21 
13. STATISTICAL CONSIDERATIONS.............................................................................................. 22 
13.1. 
Overview .......................................................................................................................... 22 
13.2. 
Sample Size, Clinical Significant Difference and Power Justification ................................... 23 
13.3. 
Analysis of Primary Endpoint ........................................................................................... 26 
13.4. 
Analysis of Secondary Outcomes ................................................................................... 26 
13.5. 
Analysis of Exploratory Safety Outcomes: ...................................................................... 27 
13.6. 
Analysis of Subgroups ..................................................................................................... 27 
13.7. 
Analysis of Planned Interim Monitoring ........................................................................... 27 
14. STUDY ADMINISTRATION ......................................................................................................... 29 
14.1. 
Role of NHLBI .................................................................................................................. 29 
14.2. 
Executive Committee ....................................................................................................... 30 
14.3. 
Steering Committee ......................................................................................................... 30 
14.4. 
Recruitment and Study Coordination Committee ............................................................. 30 
14.5. 
Pain Management Protocols, Clinical Oversight and Implementation Committee ............ 30 
14.6. 
DSMB .............................................................................................................................. 31 
14.7. 
Committee Meeting Management .................................................................................... 31 
18. APPENDICES .............................................................................................................................. 32 
18.1 
Appendix A. Schedule of Assessments* .......................................................................... 32 
 
 

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Protocol Changes from Version 1.0 (January 8, 2019) to 2.0 (March 20, 2019) 
 
Section 8.2.2 
Changes made on page 17 to Table 1. Weight-Based Doses for Morphine Sulfate and 
Hydromorphone to capture a dose for Morphine for participants weighing less than 50Kg and to 
revise dose of Hydromorphone for participants into 3 categories rather than the original 4   
 
Sections 13.7 and 13.8 
 
Corrections made  on pages 23, 24 and 26 are to clarify that the primary outcome of change in 
pain scores is not from ED arrival to discharge, but from the time of placement in a treatment area 
to the time of disposition (hospital admission, discharged home, assigned to observation status) or 
a maximum treatment duration of 6 hours, whichever comes first. 
 
Section 13.9 
 
Correction made on page 26 is to clarify that the secondary outcome of ED length of stay is from 
ED arrival to discharge. 

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1. 
EXECUTIVE SUMMARY 
 
 
 
Title: 
A Comparison of Individualized vs. Weight Based Protocols To Treat 
Vaso-Occlusive Episodes in Sickle Cell Disease  
(COMPARE VOE) 
Location: 
6 clinical sites (Emergency Departments) in the United States 
Objectives: 
To compare the two analgesic protocols recommended by the 
NHLBI for treating VOE in the Emergency Department.  
Study Design: 
A Phase III single-blinded randomized study of approximately 460 
participants to capture data on 230 participants with one ED visit in 
the study population.  
Treatment 
Regimens: 
1:1 treatment allocation will be used with site as the stratification 
variable. Subjects will be randomized to receive analgesic 
management for VOE either via a weight-based SCD analgesic, or a 
patient-specific analgesic developed by their primary SCD outpatient 
provider. 
Primary 
Endpoint: 
Change in pain scores in the ED from the time of placement in 
treatment area to the time of disposition (hospital admission, 
discharged home or assigned to observation status) or a maximum 
treatment duration of 6 hours, whichever comes first 
Secondary 
Endpoints: 
• ED length of stay  
• Hospitalization for pain control 
• Return ED visits, hospitalizations, or day hospital visits within 
seven days of index ED visit 
 

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Study Flow Chart 
 
Screen potential participants by inclusions and exclusion criteria for 
randomization population; obtain informed consent for up to 460 
participants; randomize them to one of the two analgesic protocols; 
develop and upload the analgesic protocol in EMR
Randomization Arm 1
Patient-specific analgesic 
protocol 
Randomization Arm 2
Weight-based SCD specific 
protocol
Participant presenting to the ED for their visit due to VOE will be 
automatically enrolled to the study population with target sample size of 
230
Once treatment is started, repeat interview every 30 minutes until
the time of disposition (hospital admission, discharged home or assigned 
to observation status) or a maximum treatment duration of 6 hours, 
whichever comes first
Perform first interview once participant is placed in a treatment  area
 
 
 
2. 
HYPOTHESES AND OBJECTIVES 
 
2.1 
Primary Objectives and Hypothesis 
The primary objective of the COMPARE-VOE study is to compare change in pain 
scores in response to two different treatment regimens for treating acute painful VOE in 
SCD. All patients will be followed for a maximum of 6 hours in the ED, or until time of 
placement in observation status, discharge or inpatient admission. 
Our primary hypothesis is that that the patient-specific analgesic protocol is superior to 
the weight-based analgesic protocol. A sample size of 230 subjects with ED visits 
provides 90% power to detect a 14-mm clinically significant reduction in pain scores 
between the two groups with 0.05 type I error using a horizontal Visual Analogue Scale 
100 mm in length. This assumes the same standard deviation (SD) of 31 mm in pain 
score reductions in the two groups while accounting for 10% missing data rate. 
 
2.2 
Secondary Objectives 
The secondary objectives of this study protocol will be the following endpoints: 

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• ED length of stay  
• Hospitalization for pain control 
• Return ED visits, hospitalizations or day hospital visits within seven days of the index 
ED visit 
 
 
3. 
BACKGROUND AND RATIONALE  
 
Burden of SCD: Sickle cell disease (SCD) is a genetic disorder and the most common 
hemoglobin disorder in the United States (U.S.). It affects an estimated 90,000-100,000 
Americans and was ranked as the fifth most common principal diagnosis for Medicaid’s 
super-utilizer hospital stays (super-utilizers have 4 or more hospital stays in 1 year) in 
2012.9 SCD affects vulnerable populations, occurring in 1 in 365 African American births 
and 1 in 16,305 Hispanic American births in the U.S.10 Although data reported in 2013 
cite an improvement in childhood mortality,11 the median age of death in 2005 was 38 
and 42 years for males and females, respectively.12 These mortality figures are 
essentially unchanged from data published in the mid-1990s, and result from increased 
mortality in early adulthood, as youth transition from the pediatric to the adult-oriented 
health system.13, 14 Causes of death include stroke, sepsis, acute chest syndrome, and 
multi-system organ failure.14 However, painful vaso-occlusive episodes (VOE) are the 
most common manifestation of SCD experienced by patients and the most common 
reason for ED visits.7 Severe VOE has been defined as a new onset of pain (7/10 or 
greater) for at least four hours for which there is no other explanation than vaso-
occlusion, requiring treatment with parenteral opioids or with ketorolac.1 The cause of 
VOE relates to abnormal red blood cells. Under conditions of stress and de-oxygenation, 
red cells change shape and are unable to deliver sufficient oxygen to the tissues. This 
results in tissue ischemia and debilitating pain. Pain from VOE occurs suddenly, is 
excruciating and unpredictable.15 VOE often requires treatment in an ED and patients 
with an increased frequency of VOE have higher morbidity and mortality rates.16 It is 
critical that patients with VOE receive evidence-based, timely pain relief. (Of note, VOE 
was historically referred to as vaso-occlusive crisis (VOC)).  
 
Current Evidence Base for ED Management of VOE: As demonstrated by the recent 
national survey of emergency physicians (ACEP survey), treatment of VOE is variable 
and only 12% of ED physicians reported using the National Heart, Lung and Blood 
Institute (NHLBI) recommendations to treat VOE.6 This lack of guideline use may be due 
in part to the lack of evidence on how to best treat VOE. In one pediatric ED, 
improvement in pain scores and hospital admission rates were seen over a period of six 
years after the implementation of pediatric patient-specific analgesic protocols 4. In a 
second pediatric ED, the use of a weight-based VOE analgesic protocol and use of intra-
nasal fentanyl resulted in improved time to initial and repeat analgesic administration, as 
well increased number of children being discharged home.5 While these findings are 
encouraging, both projects were conducted in pediatric EDs. Our R34 is the only study 
directly comparing weight-based and patient-specific analgesic protocols for VOE in 
adult EDs.21 Patient-specific analgesic protocol development and maintenance is labor 
intensive; high-level evidence will be required to support widespread dissemination. 
 

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Patients Perception of ED Treatment of VOE:  Given the lack of both a standard of 
care, or evidenced-based analgesic protocols to treat VOE, it is not surprising that in the 
ED, SCD patients often report dissatisfaction with care. In a recent cohort study, 81% of 
patients reported choosing to stay at home to manage their VOE, and of those, 83% 
reported that past negative ED experience influenced this decision.3 However, patients 
often require treatment in the ED to not only manage pain but also because other 
serious complications may exist that require immediate evaluation and treatment.20 ED 
management of VOE must be evidence-based.   
 
NHBLI Recommendations for ED Management of VOE: NHLBI recognized the need 
to provide evidence-based recommendations for SCD, including VOE. In September 
2014, NHLBI formed an expert panel that published 17 recommendations for treatment 
of VOE Dr. Tanabe was an invited member of the panel. None of the recommendations 
supports the current variability in practice. Only one recommendation (use of opioids) 
was supported by high-level evidence with a strong recommendation.8 The remaining 
recommendations do not have supporting high-level evidence. A key recommendation 
was the use of patient-specific analgesic protocols for pain management. When 
unavailable, a standard VOE analgesic protocol specific for SCD was recommended. 
However, NHLBI did not define “standard analgesic protocol”. In a 2015 review of the 
NHLBI recommendations, specific gaps, as well as the need for additional research were 
identified. The need to conduct research to compare and assess the value of patient-
specific and weight-based analgesic protocols for VOE was indicated as a priority 
research area,2 which this Phase III RCT aims to address. 
 
Significance of this Study: Sickle cell disease (SCD) is a chronic disease associated 
with many medical problems, especially the severe pain referred to as vaso-occlusive 
episodes (VOE) that leads to an emergency department (ED) visit. We do not know the 
best way to treat painful VOE in the ED. This phase III randomized clinical trial will 
identify the best analgesic approach for treating adult SCD patients with VOE during an 
ED visit. It will determine whether the patient-specific analgesic approach is superior to 
the weight-based analgesic approach in decreasing the severe pain due to VOE. The 
trial’s results will shape the health care paradigm for the thousands of SCD patients 
suffering from severe pain. 
 
 
4. BASIC STUDY DESIGN  
 
A multi-site Phase III, single blinded, RCT will be conducted to address the study aims. 
The trial will be conducted at six U.S. sites, with an enrollment period of 24 months. 
Approximately 460 patients will be consented and randomized in order to obtain the study 
population of 230 patients with at least one ED visit.   
 
The modified intent to treat (ITT) population is adult SCD patients with an ED visit due to 
VOE. The primary outcome will be change in pain scores from the time of placement in a 
treatment area to the time of disposition (hospital admission, discharged home or 
assigned to observation status) or a maximum treatment duration of 6 hours, whichever 

13 
 
comes first. Due to the logistical difficulty in consenting and randomizing patients during 
an ED visit due to VOE (see Section 7.2), we plan to screen, consent, and randomize 
patients in a larger population than the target population of adult SCD subjects with ED 
visits. There is no reason to think the patients randomized are any different from those 
who eventually do have an ED visit for VOE. The occurrence of VOE is very unpredictable 
and not related to overall disease severity. Consented adult SCD patients will be 
randomized to receive analgesic management for VOE via a weight-based SCD analgesic 
protocol, or via a patient-specific analgesic protocol developed by their hematologist/sickle 
cell team, which will be used in the patient’s future ED visit due to VOE.  
 
Patients will be told what drug and dose they are receiving during their study ED visit, 
however, they will remain blinded to which analgesic protocol they are randomized. The 
primary difference between the two analgesic protocols is the starting opioid dose. Other 
elements of both analgesic protocols reflect the recommendations in the NHLBI expert 
panel recommendations document, including recommended route and re-dosing intervals. 
All analgesic protocols, patient-specific and weight-based, will be written by the SCD 
provider and uploaded to the electronic medical record (EMR) prior to an ED study visit. 
 
 
5. 
STUDY POPULATION AND ELIGIBILITY CRITERIA 
 
5.1 
Population for Randomization 
The population for randomization is adult SCD patients with the following Inclusion and 
Exclusion criteria. 
 
The selection criteria below were designed to be inclusive and representative of the SCD 
population, including appropriate representation of women.   
 
5.1.1. 
Inclusion Criteria  
1) > 18 years of age 
2) SCD patients with the following genotypes: 
a. Hgb SS, SC and SB+, SB- thalassemia 
 
5.1.2. 
Exclusion Criteria 
1) Patients with sickle cell trait 
  2) Patients with a treatment protocol that does not allow administration of opioids 
  3) Patients with an existing ED protocol that includes oral opioids only  
  4) Patients prescribed buprenorphine-containing medication in the outpatient 
setting 
5) Patients prescribed methadone 
 
5.2  
Population for Enrollment  
The population for enrollment is randomized patients with the following inclusion 
and exclusion criteria. 
 

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5.2.1. 
Enrollment Inclusion Criteria:  
1) Patient is randomized 
2) ED visit for VOE requiring parenteral opioid analgesia 
 
5.2.2. 
Enrollment Exclusion Criteria 
1) 
Patients presenting to the ED with other complications (e.g., acute chest pain, 
stroke, sepsis, priapism and other pulmonary complications) not clinically 
appropriate/stable for inclusion 
 
 
6. 
TREATMENT INTERVENTIONS 
 
6.1. 
Overview of Treatment Interventions 
This will be a single-blinded two-arm randomized clinical trial comparing: 
• Patient-specific analgesic protocol to treat VOE in adults with SCD 
• 
Weight-based analgesic protocol to treat VOE in adults with SCD 
There is currently no standard approach to managing VOE pain in the ED, resulting in 
wide variability in ED-based pain management. Patients will be randomized to either a 
patient-specific analgesic protocol or a weight-based analgesic protocol to treat VOE 
during an ED visit.  
 
6.2. 
Blinding 
The provider will be un-blinded to the analgesic protocol at the time of the patient visit to 
the ED. 
Patients will be told what drug and dose they are receiving during their study ED visit. 
However, they will remain blinded to the analgesic protocol to which they are randomized. 
The research assistant performing the study assessments will also remain blinded to the 
randomized analgesic treatment protocol until all assessments have been completed.  
 
6.3. 
Patient Safety and Concomitant Therapies 
This study will evaluate and compare analgesic treatment protocols to treat VOE in adult 
patients with SCD during an ED visit. 
 
 
7. 
RECRUITMENT AND SCREENING PROCEDURES 
 
7.1. 
Common Recruitment/Screening Procedures 
Patients meeting eligibility criteria for randomization population will be approached 
regarding participation in this study. The Site Investigators will train all research staff in 
screening and approaching patients for participation, consent, and data collection.  
Patients will be recruited during an outpatient visit at hematology/SCD clinic, during an 
inpatient hospitalization, or at the end of an ED visit. Patients will consent for participation 
in the study during a subsequent ED visit for VOE, should one occur during the study 

15 
 
enrollment period. This procedure is very effective because patients can provide a more 
informed consent when not in severe pain. It would also not be feasible to enroll patients 
during an actual ED visit because the delay in analgesia associated with consulting the 
hematologist for the immediate development of the analgesic protocol and placement in 
the EMR. Community recruitment is also not feasible because we need a local 
hematologist to write the analgesic protocol and implement it in the hospital’s EMR. 
 
Inpatient Hospital Recruitment – The study staff at each site will round daily on the 
inpatient units to recruit subjects. Patients admitted to the hospital will be approached for 
possible participation only after obtaining permission to speak with the patient from a 
member of the clinical care team. If the patient is in too much pain, the study staff will 
return at a later date/time to discuss possible enrollment. 
 
Hematology/SCD Clinic Recruitment – Study staff at each site will work closely with the 
clinic providers to determine the least intrusive manner to approach patients for 
participation and consent during routine clinic visits. All patients meeting study inclusion 
criteria will be approached for possible participation. 
 
ED Recruitment – Study staff at each site will recruit those ED patients being discharged 
home who have not previously declined participation or already not been consented for 
this study. If the patient agrees to participate, they will sign the consent to participate in 
the study during a subsequent ED visit for VOE. 
 
7.2 
Estimated Enrollment Period 
 
This study will randomize approximately 460 patients at approximately six U.S. study sites 
in order to enroll 230 subjects with an ED visit for VOE in the study population. The 
projected timeline for enrollment is approximately 24 months. 
 
 
8. 
INITIAL STUDY EVALUATIONS AND RANDOMIZATION 
A complete schedule of assessments throughout the study is provided in Appendix A. 
 
8.1. 
Screening for Informed Consent and Patient Randomization 
Potential trial patients believed to meet study selection criteria for the randomization 
population will be approached and willing patients will be consented for trial participation. 
After providing informed consent and signing the informed consent form (ICF), trial 
eligibility criteria will be formally confirmed. Patients will be randomized. Patients’ 
characteristics will be collected at the time of randomization. After we have reached the 
target ED visit sample size in the study population, we will notify the patients remaining in 
the randomization population by phone, a subsequent clinic visit or by mail that the study 
enrollment has been completed and their randomized analgesic protocol will be removed 
from the EMR. 
 
 
8.2. 
Randomization and Patient Analgesic Protocols  
After patients have provided informed written consent, they will be randomized to either 

16 
 
the weight-based analgesic protocol or a patient-specific analgesic protocol that will be 
developed by their hematologist/sickle cell team. A 1:1 treatment allocation will be used 
with site as the stratification variable. A computer-generated permuted block 
randomization schedule with stratification by clinical site will be prepared by the DCC 
senior statistician with block size randomly chosen that will not be revealed to 
investigators. This scheme provides chronological balance during enrollment with respect 
to the number of patients allocated to each treatment arm, and thus balances the 
treatment groups with respect to possible changes in the mix of patients over time. For the 
sites, the randomization will be available through the password protected and customized 
web-based electronic data capture (EDC) system. The EDC will be maintained by the 
DCC data management team. Treatment plans can be updated as needed by the 
hematologist. 
 
8.2.1 Patient-Specific Analgesic Protocol 
If the patient is randomized to the patient-specific analgesic protocol, the outpatient SCD 
provider will develop a patient-specific analgesic protocol based upon chronic opioid 
therapy, if relevant, and past successful ED treatment. The procedure for developing 
patient-specific analgesic protocols is as follows: A member of the outpatient SCD 
provider team will review the patient’s medical record to determine: 1) the patient’s 
maximum home opioid dose, and 2) previous ED analgesic medication(s) and doses that 
have been effective and safe in the past.  
 
Starting Dose determination:  
Step 1: Calculate maximum home opioid dose and determine initial intravenous (IV) / 
subcutaneous (SC) ED VOE dose. IV and SC doses will be identical.  
Maximum home opioid dose is defined as the maximum dose of prescribed opioids 
typically taken by the patient at home in any 24-hour period. The maximum will be 
calculated by combining all long acting and short acting opioids taken within a 24-hour 
period and converting that medication to IV morphine sulfate equivalents (IVMSE). The 
SCD team member will use the maximum home opioid dose to generate a suggested 
starting dose of IV opioid for severe VOE pain in the ED as follows: preliminary calculation 
of IV dose for next ED visit (based on home opioid consumption) = 20% of patient’s 
maximum 24-hour home opioid dose converted to IV morphine and IV hydromorphone. 
 
Step 2: Reconcile with past ED doses.  
The first choice of opioid (Morphine or hydromorphone) will be based on review of the 
patient’s medical record for pertinent medical history and which drug has been used in the 
past with greater success. The preliminary calculations above will then be compared to 
doses of opioids that have been administered to the patient in the ED in the past. If the ED 
doses and the calculated preliminary doses are within 10% of each other, the preliminary 
dose will be finalized for that patient’s suggested patient-specific analgesic protocol for 
use at the next ED visit for VOE. If the discrepancy is greater than 10%, the SCD team 
member will adjudicate this case with the Pain Management Protocols, Clinical Oversight 
and Implementation Committee to choose a safe dose in the following manner. Whichever 
of the two doses (preliminary calculations based on home consumption or prior ED doses) 
is lower will be chosen as the final suggested dose for use at the next ED visit. The lower 
dose was chosen because it is perceived to be safer. In addition, dose escalation is 

17 
 
permitted at the SCD provider’s discretion. For example, if the highest prior ED dose is 
less than half of the preliminary calculated dose, the highest prior ED dose would be 
selected and could be increased by 25% for use in the patient-specific analgesic protocol. 
However, if the previously used ED dose is less than a weight-based dose, a weight-
based dose will be used to avoid use of an unreasonably low dose. Per the NHLBI 
recommendations for the treatment of VOE, the dose frequency for IV pain medication 
administration will be set at 20-30 minutes unless the SCD provider feels this is not safe. 
 
8.2.2 Weight-Based Analgesic Protocol 
The NHLBI recommendations will be used to develop the weight-based analgesic 
protocol; there are some similarities to the patient-specific analgesic protocol, namely 
dosing intervals and routes. The NHLBI recommendations include a starting dose be 
based on prior analgesic use. This can be difficult for a patient to accurately report at 
times. ED providers are typically not proficient in calculating and converting oral, or patch, 
opioid dosing to intravenous doses and are unlikely to do this on a widespread, national 
basis. Instead, we opted to make one adaptation to the expert panel recommendations for 
a “standard” VOE protocol; the initial dose will be weight-based. We chose weight-based 
because there is no current “standard” VOE protocol and weight-based opioid dosing is an 
acceptable alternative in other pain conditions, including cancer. As recommended by the 
NHLBI guidelines, the weight-based analgesic protocol will include re-assessment and re-
dosing every 20-30 minutes, with one possible dose escalation of 25%. Table 1 provides 
an example of typical weight-based doses. A 5:1 conversion of morphine sulfate to 
hydromorphone (7.5 mg:1.5 mg morphine sulfate to hydromorphone) was used to 
calculate doses for both the weight and patient-specific doses.30 
 
 
Table 1. Weight-Based Doses for Morphine Sulfate and Hydromorphone 
 
Weight range (kg) 
Morphine dose (mg) 
<50 
4 
50 – 69.9 
6 
70 – 89.9 
8 
> 90 
10 
Weight range (kg) 
Hydromorphone dose 
(mg) 
 <60 
1 
 
 
60 – 89.9 
1.5 
> 90 
2 
 
 

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8.3 Odd Volume Doses for both analgesic protocols: One barrier to analgesic protocol 
implementation was the odd doses that resulted in the need to administer a volume of 
drug less than the amount in which it was supplied. This required “wasting” by the ED 
nurses and verification by a second nurse. We have consulted with a multidisciplinary 
team consisting of a pain expert, adult hematologist, and an emergency department 
physician to determine a strategy to select a final dose that will minimize the need for odd 
doses and wasting procedures (e.g. morphine 4.3 mg, or hydromorphone 1.3 mg). All 
doses of morphine can be ordered in increments of 2 mg and doses of hydromorphone 
can be ordered in increments of 0.5 mg. These doses remain consistent with the patient-
specific and weight-based doses with rounding to a safe dose, and will significantly reduce 
the need to waste drug in most cases. We used this information when creating Table 1.  
Table 2 describes differences between analgesic protocols in agent, dose, route, 
monitoring, repeat doses and hydration. The primary difference between analgesic 
protocols is dose and the provision to increase weight-based doses if insufficient pain 
relief. 
Table 2:  Comparison of NHLBI Recommendations: Patient specific vs. Weight-based analgesic 
Protocol 
 
Patient-specific analgesic protocol 
Weight-based SCD analgesic protocol 
Agent 
To be determined (TBD) by SCD provider after 
randomization for use at a future ED visit 
(morphine sulfate or hydromorphone) 
To be determined (TBD) by SCD provider 
after randomization for use at a future ED visit 
(morphine sulfate or hydromorphone) 
Dose 
TBD a priori by SCD provider, based upon 
current outpatient opioid therapy, if applicable, 
and past doses required to treat VOE during past 
ED visits or hospitalizations.   
TBD a priori by SCD provider. 
Initial dose = weight based  
hydromorphone 0.02 mg/kg  
morphine sulfate 0.1 mg/kg 
Route 
Intravenous (IV) unless unable; 
Sub-cutaneous when IV access is difficult. 
Intravenous (IV) unless unable; 
Sub-cutaneous when IV access is difficult. 
Monitoring 
Per routine standard of care 
Q 30 minutes per research protocol / research 
assistant (sedation level, SpO2, BP, HR, RR). 
Per routine standard of care  
Q 30 minutes per research protocol / research 
assistant (sedation level, SpO2, BP, HR, RR). 
Repeat doses 
TBD by SCD provider – Q 20-30 minutes as 
required to treat unrelieved pain.  No maximum 
dose set. 
Q 20-30 minutes for unrelieved pain.  
All additional doses, if required, may be 
provided at the same dose as the 1st dose, or 
no more than a one time 25% increase above 
the original dose. 
Intravenous 
hydration 
Maintenance rate (unless dehydrated) when 
patients are unable to drink fluids adequately. 
Maintenance rate (unless dehydrated) when 
patients are unable to drink fluids adequately.  
 
Once the patient’s analgesic protocol has been developed (patient-specific or weight-
based) by the hematologist/sickle cell team, the research team will be notified. The 
research team will ensure the analgesic protocol is uploaded to the electronic medical 
record (EMR) within one week of receipt. The analgesic protocol will be available in the 
EMR for future ED visits.  
 
9. 
STUDY ENROLLMENT AND COMPLETION AT ED VISIT 
 
When the randomized patient has an ED visit for VOE, this patient is enrolled in the study 
population. The provider (un-blinded) in the ED will access the patient’s randomized 
analgesic protocol from the EMR for treatment. The patient will only be told what drugs 
and doses they will receive, but will not be told which analgesic protocol (weight-based or 
patient-specific) to which they have been randomized, thus the patient is blinded to the 
randomized arm. Research assistants (RAs), who are also blinded to study arm, will 

19 
 
interview the patient during an ED visit to obtain pain score data for the primary outcome. 
Only one ED visit per patient is recorded for the primary and secondary outcomes. The 
study is complete as soon as one post-randomization ED visit is recorded. The patient’s 
randomized analgesic protocol will be removed from the EMR after the study ED visit is 
recorded. In the event where the ED visit is missed due to no availability of a RA (e.g., in 
the middle of the night), the next ED visit will be recorded. The RA will periodically review 
the EMR to obtain information on the missed ED visits for tracking purposes. During the 
ED visit, the maximum amount of time for study participation is six hours, which begins at 
placement in an ED treatment area. A brief interview will be conducted every 30 minutes 
until 1) discharge home, 2) admission to the hospital or assigned to observation status 
for continued pain management, or 3) after six hours of treatment (maximum data 
collection period), whichever comes first. Each patient will be allowed to contribute only 
one ED visit to the study data. 
 
 
10. 
FOLLOW-UP DATA COLLECTION. 
 
After the completion of the patient’s recorded ED visit, the RA will periodically review the 
EMR to obtain the number of ED visits and number of hospitalizations within 7 days of 
the recorded ED visit for collection of secondary outcomes. 
 
 
11. OUTCOME DETERMINATIONS 
 
1.1 
Primary Endpoint 
The primary endpoint of the study population is the change in pain scores from the time of 
placement in a treatment area to the time of disposition (hospital admission, discharged 
home, assigned to observation status) or a maximum treatment duration of 6 hours, 
whichever comes first. 
 
1.2 
Secondary Endpoints 
The secondary outcomes of the study population include the following:  
• ED length of stay  
• Hospitalization for pain control 
• Return ED visits, hospitalizations, or day hospital visits within seven days of the index 
ED visit 
 
12. 
PARTICIPANT SAFETY AND ADVERSE EVENTS 
 
12.1 
Institutional Review Boards 
All sites will submit the study protocol, informed consent form, and other relevant study 
documents to the Central Institutional Review Board (IRB) for approval. 
 
12.2 
Informed Consent 
A signed ICF is a requirement for patient inclusion in the study. All patients will have the 

20 
 
purpose of the study, the study interventions and evaluations, and the potential risks and 
benefits of participation explained to them and their questions answered. If patients 
consent to participation in this study, they will review and sign the ICF. Study staff at the 
enrolling site will administer the ICF during hospitalization, a clinic or at the end of an ED 
visit (for enrollment in future ED visits). At the time of ICF discussion, patients will receive 
study informational materials and the contact information for the site study staff at the 
enrolling site. 
 
 
12.3 
Voluntary Withdrawal from the Study 
Patients may withdraw at any time during the study without giving reasons and will not 
suffer disadvantage as a result. In cases of study withdrawal, patient care will continue per 
the discretion of healthcare providers. Investigators may withdraw patients from the study 
at any time if upon review the patient meets exclusion criteria.  
 
12.4 
Summary of the Risks and Benefits 
We do not anticipate that participation in this study will be associated with increased risk 
beyond that of standard care. Potential side effects for the medications used in the study, 
such as morphine and hydromorphone, include drowsiness and sedation, nausea, 
vomiting, light-headedness, and itching.  Less common side effects include respiratory 
depression and lower blood pressure. Both morphine and hydromorphone are currently 
used in routine clinical practice. The benefit of participation in the study is the generation 
of an evidence-based treatment analgesic protocol for SCD patients with an ED visit for 
VOE.  
 
12.5 Collection and Reporting of Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence associated with the use of a 
drug in humans, whether or not it is considered drug related. Only protocol- specific 
expected AEs occurring during the enrollment ED visit will be collected and reported on 
the AE eCRF.  
 
12.5.1 Protocol-Specific AEs 
The following events are considered expected AEs for this protocol and are reported on 
the AE eCRF.  
• Nausea 
• Vomiting 
• Pruritis 
• SPO2 < 95 % requiring supplemental use of oxygen via nasal cannula due to opioid 
therapy 
• Moderate or severe sedation 
• Drowsiness 
• Respiratory depression not requiring intubation or naloxone 
• Low blood pressure 
 
AEs are summarized and reported to DSMB in bi-annual meetings. 
 
 

21 
 
 
 
12.6 Collection and Reporting of Serious Adverse Events 
 
An adverse event is considered a serious adverse event (SAE) if, in the view of the 
investigator or sponsor, results in any of the following: death, is life threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization,* is a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, 
a congenital anomaly/birth defect, or an important medical event. Only protocol-specific 
SAEs will be collected and reported on the SAE eCRF. Specific timing on collection and 
reporting of SAEs is specified below.  
 
*For this protocol, if the study ED visit resulted in a hospitalization for pain control, this 
hospitalization will be considered the index hospitalization and will not be considered an 
SAE. Hospitalizations for VOE treatment within 7 days post the ED visits will also not be 
considered SAEs. 
 
12.6.1 Protocol-Specific SAEs 
SAEs are collected from the time of first administration of pain protocol drug during the 
study ED visit through 7 days post ED visit and reported on the SAE eCRF. The following 
SAEs are to be considered. 
• Respiratory depression requiring naloxone administration given within 2 hours of 
last administration of pain protocol drug.  
• Events resulting in death  
• Events that are considered life-threatening complications 
• Events requiring admission to Intensive Care Unit (ICU) or intubation within 7 days 
of first administration of pain protocol drug during the enrollment ED visit. 
 
SAEs occurring during the protocol administration or within 7 days post enrollment ED 
visit, along with the investigator’s assessment of relatedness, will be recorded by the site 
on the SAE eCRF in the EDC within 24 hours of knowledge of the event. The Data 
Coordinating Center (DCC) will receive an EDC email notification of SAE data once entry 
by the site. The DCC will notify the NHLBI within two business days of receipt of the email 
notification. Once notified, the NHLBI will notify the DSMB. 
 
If patients experience any SAEs during the ED visit, the treatment protocol will be 
discontinued. Subsequent VOE treatment will be determined by the ED provider.  
 
Assessment of Serious Adverse Event Causal Relationship 
The investigator must assess the relationship of any SAE to the use of the drug, based on 
available information, using the following guidelines:  
 
Not Related: There is not a reasonable causal relationship to the product and the adverse 
event.  
 
Related: There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. 

22 
 
 
Assessment of Serious Adverse Event Intensity   
The determination of serious adverse event intensity rests on medical judgment of a 
medically qualified investigator. The severity of SAEs will be graded using the following 
definitions:  
 
• Mild: awareness of sign, symptom, or event, but easily tolerated;  
• Moderate: discomfort enough to cause interference with usual activity and may 
warrant intervention;  
• Severe: incapacitating with inability to do usual activities or significantly affects 
clinical status, and warrants intervention. 
 
12.7 Expedited Reporting 
Adverse events that are assessed as serious, drug-related, and are evaluated by the site 
PI as unexpected, per the current product label, qualify for expedited reporting to the FDA. 
For the events identified as serious, drug-related, and unexpected, site investigators are 
required to complete and submit the MedWatch Online Voluntary Reporting Form (3500) 
at https://www.accessdata.fda.gov/scripts/medwatch/. 
 
12.8 Acute Chest Syndrome 
1) 
Reported Acute Chest Syndrome (ACS) events will be reviewed to verify the 
diagnosis of ACS by an adjudication committee consisting of study site investigators 
specializing in hematology and emergency medicine within 15 days of event entry into 
the Hospitalization eCRF. Each reported ACS event will be reviewed by two members 
of the committee.  If they do not agree, a third member of the committee will review the 
event and the result of the majority will be recorded. Committee members will not 
review events from their site. The adjudication results will be entered into the ACS 
eCRF by the Clinical Coordinating Center within 5 business days of the completed 
adjudication.  
13. 
STATISTICAL CONSIDERATIONS 
13.6. 
Overview 
Detailed description of the plan for statistical analysis of each endpoint will be detailed in a 
Statistical Analysis Plan (SAP) that will be prepared after the final study protocol is 
approved. The SAP will be prepared by the DCC senior statistician under Dr. Barnhart’s 
supervision.  
 
Descriptive statistics will be used to summarize patient socio-demographic and clinical 
characteristics. The analyses of primary and secondary outcomes as well as the summary 
description of pain-related side effects and safety will be carried out by the DCC statistical 
service.  Means, standard deviations, medians, 25th and 75th percentiles, minimum and 
maximum will be presented for continuous variables; the number and frequency of 
patients in each category will be presented for nominal variables. For all analyses, a two-
sided p-value ≤ 0.05 will be considered statistically significant. Analyses will be performed 
using SAS version 9.4 or higher software (SAS Institute, Inc., Cary, NC). 
 
Multiple Comparisons: With the pre-specified primary and secondary analyses, we 

23 
 
recognize that there is a multiplicity of analyses to be performed, which leads to an 
increased probability that at least one of the comparisons could be "significant" by chance.  
There are adjustments (e.g., based on the Bonferroni inequality) that can be used to 
preserve the overall type I error level. To attempt to adjust for the effects of the repeated 
significance testing that will occur as part of potential interim monitoring (discussed 
below), plus to adjust for the multiplicity of secondary outcomes, would require that very 
small significance levels be used for every comparison.  Rather than taking this approach 
we will be conservative in the interpretation of secondary analyses, taking into account the 
degree of significance, and looking for consistency across outcomes.  The actual p-value 
for each comparison will be reported to aid in the overall interpretation.  In addition to the 
pre-specified primary outcome, we will use pre-specified secondary outcomes and pre-
specified subgroups to help avoid over-interpretation and to help guard against and 
reduce the problems inherent with multiple testing.    
 
13.7. 
Clinically Significant Difference, Sample Size and Power Justification  
Clinically Significant Difference: The primary outcome for this superiority study is the 
change in pain scores from the time of placement in a treatment area to the time of 
disposition (hospital admission, discharged home, assigned to observation status) or a 
maximum treatment duration of 6 hours, whichever comes first between, two possibly 
effective treatments. The primary outcome will be measured using a 0-100 mm visual 
analog scale. Since both analgesic protocols may significantly decrease pain, we chose 
14 mm as the minimal clinically significant difference between the two analgesic protocols 
based on 1) the literature supporting an additional 14 mm pain reduction as clinically 
important relative to the weight-based analgesic protocol in patients with an initial high 
pain score17 and 2) data from our R34 trial. Todd et al.18 first explored the concept of 
“minimally clinically significant” change in pain using a 0-100 mm visual analog scale 
(VAS) in the setting of an urban county hospital emergency department with a Level I 
trauma center. In that investigation, the numeric change on the VAS was compared to the 
patients’ subjective change in pain. The investigators found that a mean change of 13 mm 
on a VAS was estimated with a patient assessment of a “little less” pain, thus an 
estimation of clinical significance in pain reduction. In a 2nd ED study19 of 74 subjects with 
vaso-occlusive sickle cell crisis, a change of 13.5 mm was estimated as the minimum 
clinically significant change based on patients describing their pain as “a little better,” 
validating Todd’s findings. Both of these studies are based on one treatment group and 
this clinical minimal change can only be used as clinically significant difference between 
two groups if the reference group is assumed to have zero change. Because the weight-
based analgesic protocol has non-zero pain reduction based on the R34 study, 13 mm is 
not used for the clinically significant difference between the two analgesic protocols. The 
IMPROVE trial20 was designed to compare two patient-controlled analgesia (PCA) dosing 
strategies in adults and children with SCD and it used 25 mm as the clinically significant 
difference between the two strategies in their design. Most relevant to our proposed study, 
Bird and Dickson17 argued that the clinically significant change for patients with high initial 
levels of pain, especially with a VAS between 67-100 mm, required a larger improvement 
in pain scores. Specifically, they reported that patients with “a lot less” pain had a mean 
(95% CI) VAS pain reduction to be 48 mm (43, 53) if initial VAS core is within 67-100 mm. 
We expect that the SCD patients with ED visit due to VOE will have a high initial pain 
score and this was the case in the R34 study where nearly all of the patients in our R34 

24 
 
reported an arrival pain score between 67-100 mm. Thus, it is important that patients must 
experience a reduction of at least 43 mm from arrival to discharge in order to feel “a lot 
less” pain. In the R34 study where we restrict data to the 1st ED visit, patients in both 
analgesic protocols achieved a clinically meaningful change of 13 mm in pain scores from 
arrival to discharge (Table 3).  
 
Table 3. Primary and Secondary Outcomes Observed from the R34 Study 
 
However, to justify the additional workload of patient-specific analgesic protocols it is 
important to justify how much better improvement in pain scores is achievable and 
meaningful, especially in the population with high arrival pain score when compared to a 
weight-based analgesic protocol. The mean VAS pain reduction was 29 mm in the weight-
based analgesic protocol in the R34 study. Thus, an additional 14 mm in pain reduction 
will bring the pain reduction to 43 mm (achieved in the patient-specific group in the R34 
study), which is the pain reduction needed (based on the lower bound of 95% CI7) to have 
“a lot less” pain for patient with an initial high pain score.  Therefore, 14-mm difference in 
pain reduction between the two analgesic protocols is chosen as the meaningful and 
clinically significant difference for patients experiencing SCD VOE with an initial high pain 
score.  
 
Sample Size and Power: The primary null hypothesis is the equality of the pain score 
reduction (from the time of placement in a treatment area to the time of disposition 
(hospital admission, discharged home, assigned to observation status) or a maximum 
treatment duration of 6 hours, whichever comes first) between the dosing protocols. A 
two-sample t-test will be used to test the primary hypothesis. A sample size of 230 
subjects with ED visits provides 90% power to detect 14-mm clinically significant 
difference of pain score reductions between the two groups with 0.05 type I error, with the 
assumptions of the same standard deviation (SD) of 31 mm in pain score reductions in the 
two groups while accounting for 10% missing data rate. Assuming that 50% of randomized 
subjects will have an ED visit during the 24-month enrollment period, we expect to 
consent and randomize a total of 460 adult SCD patients. We will continue to consent and 
randomize subjects until we have the targeted 230 subjects with ED visits, even if we 
need to consent and randomize beyond 460 patients. Table 4 provides sample size and 
power calculations for various scenarios to support our target sample size of 230 for this 
Outcomes 
Total 
(N=52) 
Patient-specific  
Analgesic 
Protocol (N=26) 
Weight-based  
Analgesic 
Protocol(N=26) 
Primary outcome: Change in pain scores 
from 
arrival 
to 
discharge 
or 
inpatient 
admission (maximum elapsed time of 6 
hours);  n, mean ±SD 
n=48, 36±30 
n=25, 43 + 31 
n=23, 29 + 27 
Secondary Outcomes: 
 
 
 
Length of the 1st ED visit in minutes,  mean 
±SD 
278±78 
302±70 
254±79 
Hospital admission in the 1st ED visit, % 
38.5% 
34.6% 
42.3% 
Returned ED visit within 7 days of the 1st ED 
visit, % 
15.7% 
19.2% 
12.0% 
Hospital admission within 7 days of the 1st ED 
visit, % 
9.8% 
11.5% 
8.0% 

25 
 
trial. 
 
Table 4. Sample size, power and total enrollment needed 
Sample 
size in study 
population 
(modified 
ITT 
population) 
Missing data 
rate 
SD in pain 
score 
reduction 
Power 
% enrolled 
with ED visit 
Total sample 
size in pre-
randomization 
population 
230 
10% 
31 
90% 
50% 
460 
230 
15% 
31 
88% 
50% 
460 
230 
5% 
31 
91% 
50% 
460 
230 
10% 
30 
92% 
50% 
460 
245 
10% 
31 
92% 
75% 
460 
230 
10% 
32 
88% 
50% 
460 
230 
10% 
33 
85% 
50% 
460 
 
The previous R34 study indicated that 49% of the subjects had at the ED visit over the 13 
months of enrollment. The observed missing data rate in pain score reduction is 8%, due 
to either missing pain score at arrival or at discharge. No enrolled patient died in the 
previous R34 study. The overall SD of the pain score reduction from arrival to discharge 
was 30, with 27 and 31 in the weight-based and patient-specific analgesic protocol 
groups, respectively. Therefore, our assumptions of 10% missing data rate and a SD=31 
in pain score reduction are conservative. With a 24-month enrollment period in this study, 
nearly double the enrollment time in the R34 study, it is conservative to assume that 50% 
of the randomized subjects will have a qualifying ED visit within the 24-month enrollment 
period. Thus, a total target sample size of 230, with 460 randomized subjects, is a 
reasonable and conservative estimate. As detailed in Table 4, we varied the missing data 
rate from 5%-10%, the SD of pain score reduction from 30-33, and percent of randomized 
subjects with an ED visit from 50% to 75%. All scenarios give 85% or higher power to 
detect a 14-mm clinically significant difference with the target sample size of 230 in the 
ITT population at 0.05 level. While the R34 study didn’t have sufficient power to detect a 
14-mm difference, the proposed study will have 90% power to detect this difference if 
outcome data is similar to the R34 study. Our sample size calculation assumes the pain 
score reduction follows a normal distribution based on data from the R34 study that 
indicated that the normality assumption was not violated.  
 
Power calculation for the secondary outcomes are performed for the target sample size of 
230 at 0.05 level. We do not expect any missing data in the secondary outcomes, as seen 
in the R34 study. For the length of ED stay from arrival to discharge, we have 83% power 
to detect a 30-minute difference in length of ED stay between the two analgesic protocols, 
assuming SD of 78. In the R34 study restricting to the first ED visit, the mean (SD) length 
time from arrival to discharge was 278 minutes (SD=78). For the secondary outcome of 
(yes/no) hospital admission in the 1st ED visit, returned ED visit or hospital admission 
within 7 days of the 1st ED visit, we use 15% as clinical significant difference. We have 
64%, 78% and 94% power to detect a 15% difference in hospitalization rates in the 1st ED 
visit, in rates of returned ED visits within 7 days, and in rates of hospital admission within 7 

26 
 
days, respectively, with 0.05 type I error. We have assumed that hospitalization rates are 
35% and 50%, the 7-day returned ED rates are 30% and 15%, and 7-day hospitalization 
rates are 20% and 5%, in the patient-specific and weight-based analgesic protocols, 
respectively. The assumptions on the hospitalization rates and the return ED visit rates 
are based on the observations in the R34 study. 
 
13.8. 
Analysis of Primary Endpoint 
The statistical comparison of the two randomized arms with respect to the primary 
outcome is comparing the means of the pain score reductions between the two arms. A 
comparison between two groups will be performed, adjusting for the initial pain score at 
ED time of placement in a treatment area, biological variables of SCD genotype, age and 
gender. This analysis will utilize linear regression with pain score reduction as the 
dependent variable and treatment indicator with pain score at time of placement in a 
treatment area as covariates (independent variables). Rejection of the null hypothesis 
stating that coefficient for the treatment indicator is zero will provide evidence for 
presence of the treatment effect. This comparison will utilize subjects with available 
measure of the primary outcome. In addition to the statistical hypothesis testing, 95% 
confidence intervals descriptively summarizing the difference in outcome between the 
two arms, as well as outcome in each arm will be computed.   
 
Missing Data: Because the outcome data are collected during an ED visit over a time 
period up to 6 hours, we don’t expect missing data due to any subject deaths during this 
time or withdrawal from the study. However, the pain score reduction may be missing if 
the pain score at thebeginning or the end is not recorded (e.g., if patient left without doing 
the interview prior to discharge or hospital admission).  We will make every effort to 
prevent missing data on pain score at the beginning and document reasons for missing 
pain score at final disposition (discharge or admission). If more than 5% of randomized 
patients have the pain score reduction missing, we will use multiple imputations in the 
primary analysis to mitigate potential bias of the complete case analysis. This analysis is 
valid under the missing at random (MAR) assumption. First, an imputation model via 
linear regression will be developed (based on available data) relating the pain score 
reduction with a collection of covariates including initial pain score, treatment indicator, 
baseline characteristics, and possible interactions of covariates with treatment.  A total of 
1000 data sets with imputations of pain score reduction utilizing the imputation model will 
be generated. Each of such data sets will be analyzed with linear regression (as 
described above), and the combined results comparing two groups will be reported by 
taking into account of variability due to multiple imputations.  
 
Sensitivity analysis: Unfortunately, the MAR assumption cannot be verified with the 
observed data alone and we will consider sensitivity analysis to examine impact of 
departure from the MAR assumptions on the treatment effect.  We will consider the best 
and worst scenarios where the worst scenario is to impute the pain score reduction to be 
zero for patient-specific analgesic protocol and observed maximum pain reduction for the 
weight-based analgesic protocol and the reverse is used for the best scenario. 
 
13.9. 
Analysis of Secondary Outcomes 

27 
 
Analysis of secondary outcomes will be carried out as follows. For the ED length of stay 
from ED arrival to discharge, a linear regression analysis similar to the primary outcome 
will be used to compare the length of stay between the two arms. For the hospital 
admission rate, chi-square test will be used to compare the admission rates between the 
two groups. For the count data (e.g., ED re-visits or hospitalizations for VOE within 7 
days after the recorded ED visit), it will be first evaluated by collapsing the data into a 
binary outcome with a cut off at zero and a chi-square test or Fisher exact test (if 
frequency is below 5 or less) to compare the re-admission rates or rate of a returned ED 
visit between the two groups.  If there is sufficient spread in the count data, a Poisson 
regression approach will be used to test for protocol differences in the count outcome.  
 
13.10. 
Analysis of Exploratory Safety Outcomes: 
The frequency with which various side effects, adverse event (AE) or serious adverse 
events (SAE) occur will be carefully tabulated and descriptively summarized.   Statistical 
comparisons of the randomized arms with respect to these events will use chi-square, 
Fisher exact or other appropriate two-sample methods depending on the nature of the 
event, interpreting such comparisons in the context of differences between the two 
randomized arms in the primary and major secondary outcomes and bringing to bear 
clinical judgment as to the relative seriousness of these side effects and various adverse 
events. 
 
13.11. 
Analysis of Subgroups 
If the data provide evidence of an overall difference in outcome between the randomized 
arms, we will examine whether the effect is similar for all patients, or whether it varies 
according to the pre-specified subgroups. We will also explore if treatment effect differs 
by enrolling clinical sites. These analyses will utilize the regression models with main 
effects and interactions between the randomized groups and pre-specified subgroup 
variables.  We recognize that in our study the power of interaction tests is low, especially 
for the site by treatment interaction. Hence, in addition to the formal assessment of 
randomized group by covariate interactions, effects of the treatments will be calculated 
and displayed (with 95% CI) for the pre-specified subgroups of patients.  These 
descriptive summaries will be carefully interpreted in conjunction with the formal 
interaction tests.  The following variable are used to pre-specify subgroups in the 
subgroup analyses: gender, age (< 30, ≥ 30 years old), genotypes (Hgb SS, SC, SB+, 
SB-), route (IV or SC), use (yes/no) of NSAIDS, drug administered, number of repeated 
doses, and total administrated milligrams of drug. In the R34 study, the IV route was 
administrated in over 95% of subjects. The subgroup analysis by route will not be carried 
out if 90% or more subjects receive the IV route.  
 
13.12. 
Analysis of Planned Interim Monitoring 
For ethical reasons, an interim examination of key safety data will be performed at 
regular intervals during the course of the trial. In addition, the interim monitoring will also 
involve a review of the SD of the primary outcome for a blinded sample size re-
estimation; as well as patient recruitment, compliance with the study protocol, status of 
data collection, and other factors which reflect the overall progress and integrity of the 
study.  The interim results will be carefully and confidentially reviewed by the DSMB.  No 

28 
 
efficacy analysis is planned in this trial unless it is requested by the DSMB and after 
careful discussion with the Executive Committee. Two interim analyses for futility using 
conditional power approach will be conducted when approximately one-third (N~77 
patients with ED visits) and two-thirds (N~154 patients with ED visits) of the total 230 
patients in the modified ITT population have completed the ED visits with measurements 
on the primary outcome. This timeline can be altered based on the input from the DSMB. 
The goal of the interim analysis is to determine whether to stop the trial early because it 
is unlikely to show superiority. If the conditional power falls below 10% then the DSMB 
may consider recommending to stop the trial due to futility. To reduce the likelihood of an 
underpowered study due to incorrect sample size assumptions, a blinded sample size re-
estimation will be conducted at the time of the two planned futility analyses. The sample 
size re-estimation plan is for the sole purpose of avoiding an underpowered trial due to a 
higher SD of pain score reduction or higher missing data rate than assumed. It is not for 
interim testing of a treatment effect. The two interim analyses for futility and the blinded 
sample size re-estimations will be carried out by the senior statistician under the 
supervision of Dr. Bigelow. Dr. Bigelow will be blinded to the observed trend of treatment 
effect and will present the conditional powers under different scenarios of treatment trend 
for the remaining subjects to the DSMB. Even if the formal futility interim analyses are 
presented to the DSMB, the DSMB will consider all the relevant issues related to a 
potential decision to stop the trial and most likely will not base such a decision entirely on 
the statistical arguments.  
 

29 
 
 
14. 
STUDY ADMINISTRATION 
 
An overview of the organizational structure is presented below in Figure 1. 
 
 
National Heart Lung and Blood Institute
NHLBI Project Officer – 
NHLBI Project Scientist - 
DSMB
Executive Committee
NHLBI Project Officer, NHLBI Scientist, CCC PI, DCC PI
STEERIING COMMITTEE
Chair CCC PI
Co-Chair DCC PI
NHLBI Project Scientist
Dr. Strouse
Dr. Freiermuth
Site PIs
DSMB Reporting
Dr, Bigelow
Site Engagement, Training, 
Coordination and Monitoring 
COMPARE-VOE
Clinical Site Network
Henry Ford Hospital
Wayne State University
Carolinas Healthcare Systems
University Hospitals Cleveland Medical Center
University of Maryland
University of Texas Southwestern
COMPARE-VOE
Data Coordinating Center (DCC)
Principal Investigator: Dr. Barnhart
Project Management
Clinical Data integration
(Data Management)
Statistical Services
Site Management and 
Clinical Monitoring
Safety Surveillance
Regulatory Affairs
Communications and 
Information Technology
COMPARE-VOE
Clinical Coordinating Center (CCC)
Principal Investigator: Cr. tanabe
Committee Meeting Management
Recruitment and Safety 
Coordinator Committee
Pain Management Protocols, 
Clinical Oversight and
 Implementation Committee
 
 
 
14.6. 
Role of NHLBI  
The NHLBI project officer will appoint a Project Scientist who will participate actively in study 
leadership in conjunction with the CCC and DCC PI, and Site Investigators. The project 
officer will participate in final protocol and site approvals, monitoring study progress, attend 
and participate in meetings of the Executive Committee, Steering Committee, and DSMB. 
 
 

30 
 
14.7. 
Executive Committee  
The executive committee is the decision and policy making body of the study with 
oversight in the day to day activities and overall direction of COMPARE-VOE. The EC will 
review and have final sign-off on the study protocol, manual of operations (MoP), risk-
based monitoring plan, approval of final study sites, all site materials, data management 
plan and statistical analysis plan (SAS). On issues regarding a vote, one vote per member 
will be allowed. The committee will meet at least once per year in person at the annual 
NHLBI Sickle Cell Disease research meetings in August or as designated by NHLBI. The 
committee will be composed of the chair of the COMPARE-VOE Steering Committee, the 
NHLBI Project Scientist/ Program Official/Scientific Advisor and the principal investigator 
of the DCC. This group will convene bi-weekly by teleconference alternating with the 
Steering Committee calls. 
 
14.8. 
Steering Committee  
The Steering Committee will include the CCC and DCC PIs, a SCD hematologist, an ED 
physician, the six study site Co-I’s, as well as the NHLBI Project Scientist/Program 
Official/Scientific Advisor. Dr. Tanabe (CCC PI) will serve as the Chair, and Dr. Barnhart 
as Co-Chair. The Steering Committee will assume overall responsibility for all aspects of 
COMPARE-VOE, including the design and conduct of the studies, quality control, data 
analysis, and publications. Other supporting committee’s from the CCC will report to the 
SC. The SC will meet monthly and will occur by webinar. The COMPARE-VOE SC will 
meet face-to-face at a scheduled time during the yearly investigator meetings held 
annually at Duke; this meeting will not conflict with other agenda items. The steering 
committee will provide clinical oversight and review side effect data on a monthly basis. 
The SC will develop a publication plan including specific papers, journals, and authorship 
criteria. Each member has one vote on the COMPARE-VOE Steering Committee and 
decisions will be determined by a majority vote. 
 
14.9. 
Recruitment and Study Coordination Committee 
The role of this committee is to monitor recruitment and study site data collection. 
Specifically, this group will report and discuss recruitment progress and challenges, as 
well as progress and challenges with data collection during ED visits. This committee 
consists of all study site project coordinators, study monitors and project coordinator at the 
CCC. The site coordinators have enormous responsibility for the smooth operation of the 
project. Each site investigator will be asked to lead this committee for 6-9 months 
throughout the length of the project. The committee will bring any operational issues to the 
Steering Committee and implement decisions by the Steering Committee. They will begin 
meeting in year 1 approximately 3 months before enrollment begins and will meet at least 
monthly. Either Dr. Tanabe or Barnhart will also attend these meetings. 
 
14.10. 
Pain Management Protocols, Clinical Oversight and Implementation 
Committee 
The purpose of this committee is to 1) finalize the pain management protocol, 2) develop 
the pain management protocol training for site hematologists and ED physicians and 
nurses and 3) provide clinical oversight during implementation. The committee will meet 
bi-monthly until the study protocol is finalized and monthly thereafter. A designated ED 
nurse (see LOS) at each site will participate in these meetings and lead the training of the 

31 
 
nursing staff at each site. The committee will bring any operational issues to the Steering 
Committee and implement decisions by the Steering Committee. 
 
14.11. 
DSMB 
A DSMB will be appointed by the NHLBI in collaboration with Drs. Tanabe and Barnhart for 
the COMPARE-VOE trial. The DSMB will be to monitor patient safety and review the 
performance of the study. The DSMB will be responsible for providing recommendations 
regarding trial’s conduct and guidance to ensure the safety and well-being of participating 
patients. The composition of the DSMB will be specified in the overall DSMB Charter for 
the study. 
 
14.12. 
Committee Meeting Management  
The Project Coordinator for the CCC will be responsible to schedule, coordinate, record, 
and distribute agendas and minutes from all meetings including the Executive Committee, 
Steering Committee, Recruitment and Study Coordination, and Pain Management 
Protocols and Oversight Committees. Responsibility will include identification of optimal 
meeting times and a web-based meeting platform including a conference call number and 
ability to view and share a computer screen. For in-person meetings the Project 
Coordinator will find the venue, reserve meeting rooms and audio-visual equipment, 
develop and circulate agendas, and distribute and archive meeting minutes 
 
15. 
ETHICS AND GOOD CLINICAL PRACTICE 
 
This study must be carried out in compliance with the study protocol. These procedures 
are designed to ensure adherence to Good Clinical Practice, as described in the following 
documents: 
 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice (ICH E6) 1996. 
US 21 Code of Federal Regulations Title 45 Part 46 Protection of Human Subjects dealing 
with clinical studies (including parts 50 and 56 concerning informed consent and IRB 
regulations). 
 
Participating investigators agree to adhere to the instructions and procedures described in 
the study protocol. This study protocol was designed to conform to principles of Good 
Clinical Practice and investigators agree to adhere to these principles. 
 

32 
 
 
18. APPENDICES 
 
18.1 
Appendix A. Schedule of Assessments* 
 
 
Screening/ 
Enrollment 
Randomization 
ED Visit 
Day 7 Post  
ED Visit 
Informed Consent 
(Site study staff) 
X 
Inclusion/exclusion 
criteria confirmed 
X 
X 
Pain evaluation 
questions 
X* 
ED medication 
administration; 
Recording on names 
of drugs, doses and 
timing of 
administration.  
X 
AE 
X 
 
SAE 
X 
X 
Return ED visits 
 
X 
Hospitalizations 
 
X 
Day Hospital Visits 
 
X 
 
* Assessments are to be performed Q 30 minutes (+/- 15 minutes). Assessments missed due to 
participant clinical care requirements will not be  considered deviations.  
 
 
 
 
 
 
 
 
 
 
 
 
 

33 
 
 
 
 
 
 
 
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