Clinical trial NCT03933397
Conditions: Sickle Cell Disease
Sponsor: Duke University
Start date: 2019-08-13; Completion date: 2022-05-20
Enrollment: 328 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to compare two different ways to give opioid pain medicine to treat sickle cell disease pain that is bad enough to go to the emergency department for treatment. One way uses your weight to decide how much pain medicine to give you while in the emergency department. This is called weight based treatment. The other way uses how much pain medicine you take at home and how much medicine you needed during past emergency department visits to decide how much medicine to give you. This is called patient specific treatment.

Detailed description:

Arms: arm 1: Patients assigned to this treatment protocol will be given pain medicine(s) based on the pain medicine(s) they take at home, what was needed during their past hospital and emergency department visits to treat pain and doses that have been effective and safe in the past. arm 2: Patients assigned to this treatment protocol will be given pain medicine(s) based on their weight.
Interventions: intervention 1: Patient-Specific Protocol intervention 2: Weight-based Protocol intervention 3: Morphine intervention 4: Hydromorphone
Intervention descriptions: intervention 1: Patients assigned to this treatment protocol will be given pain medicine(s) based on the pain medicine(s) they take at home for pain and what was needed during their past hospital and emergency department visits to treat pain. Medicines will include opioids, either morphine or hydromorphone. 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. The patient's regular hematologist/sickle cell team will write the treatment plans. Medications will be given every 20-30 minutes for up to 6 hours. intervention 2: Patients assigned to this treatment protocol will be given pain medicine(s) based on their weight. Medicines will include opioids, either morphine or hydromorphone. Plans will be written by the patients regular hematologist/sickle cell team. intervention 3: 4 mg for participants weighing \<50 kgs, 6mg for participants weighing 50-69.9 kgs, 8mg for participants weighing 70 - 89.9 kgs and 10mg for participants weighing greater than or equal to 90 kgs. dose is given. Re-dosing is every 20-30 minutes up to 6 hours with one possible dose escalation of 25%. intervention 4: 1 mg for participants weighing \<60 kgs, 1.5 mg for participants weighing 60 - 89.9 kgs, and 2 mg for participants weighing greater than or equal to 90 kgs. dose is given. Re-dosing is every 20-30 minutes up to 6 hours with one possible dose escalation of 25%.

Protocol documents:
ICF_000.pdf: 
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INFORMED CONSENT FORM AND HIPAA AUTHORIZATION 
TITLE: 
PROTOCOL NO.: 
NCT NO.:
SPONSOR: 
A Comparison of Individualized vs. Weight Based Protocols 
to Treat Vaso-Occlusive Episodes in Sickle Cell Disease 
IRB Protocol # 20191554 
NCT03933397
National Heart, Lung, and Blood Institute National Institutes 
of Health 


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CONCISE SUMMARY 
The purpose of this research study is to compare two different protocols for opioid pain 
medicine to treat sickle cell disease pain that is severe enough to send patients to the 
emergency department for treatment. One way uses your weight to decide how much 
pain medicine to give you while in the emergency department. This is called weight 
based treatment.  The other way uses how much pain medicine you take at home and 
how much medicine you needed during past emergency department visits to decide 
how much medicine to give you. This is called patient specific treatment. 
You will be in the study until you have an emergency department visit for your sickle cell 
disease pain that uses the weight based treatment or patient specific treatment or until 
the study ends in two years. During your emergency department visit, the doctor can tell 
you what pain medication you are getting (morphine or hydromorphone) but cannot tell 
you if you are on the weight based treatment or the patient specific treatment.  
Your participation will end when you are discharged to home, or if you are admitted to 
the hospital, transferred to the observation unit or until you have been in the emergency 
department for 6 hours – whichever comes first. You will be asked questions about how
you are feeling and about your pain.  The research assistant will write down your blood 
pressure, heart rate, breathing rate and oxygen levels.  
Seven days after your emergency department visit, the research assistant will look at 
your medical record to see if you were admitted to the hospital, had any emergency 
department visits or day hospital visits. There are risks to the drugs used in this study. 
The risks are described in this document. Some risks include nausea/vomiting, itching, 
drowsiness, light headedness, low blood pressure and slowed breathing. 
If you are interested in learning more about the study, please continue to read the 
information in this form. 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
You are being asked to take part in this research study because you have sickle cell 
disease (SCD) and may have to go to the Emergency Department (ED) in the future for 
sickle cell disease pain.  Research studies are voluntary. This means you are free to 
decide if you want to be in the study.  This document may contain words and 
information that you do not understand.   Please ask your study doctor or study staff to 
explain anything that is not clear to you.   We encourage you to talk with your family and 
friends before you decide to be in the study.  Side effects (bad reactions to the drugs 
you are given) may occur. Other important information about the research study is listed 
below. 
Please tell the study doctor or study staff if you are taking part in another research 
study. 


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This study is paid for by a grant from the National Institutes of Health (NIH).  Portions of 
the study doctor and Dr. Paula Tanabe’s (PhD) at Duke University, Dr. Huiman 
Barnhart’s (PhD) at Duke University and their research teams at Duke University’s 
salaries will be paid by this grant. <<CF-Main Financial Disclosure>> 
 
WHY IS THIS STUDY BEING DONE? 
Management of bad pain from sickle cell disease is the most common reason for sickle 
cell patients to visit the emergency department. There are many ways to treat bad pain 
from sickle cell disease in an emergency department that are not based on research.  
Many times, patients who come to the emergency department with sickle cell pain feel 
that they do not have enough pain control. The purpose of this study is to compare two 
ways to treat bad pain in the emergency department for adults with sickle cell disease. 
Neither clinically relevant research results nor individual research results will be 
disclosed to you. This study is considered investigational.  
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
The study is for about 460 adult sickle cell disease patients with an emergency 
department visit for bad pain. The study will be done at six different hospitals in the 
United States. After 230 adults have an emergency department visit for bad pain, the 
study will end. Those who are a part of the study but did not have an emergency 
department visit will be told by phone, a later clinic visit or by mail that the study is over. 
 
WHAT IS INVOLVED IN THE STUDY? 
Study Enrollment 
If you decide to be in this study, you will be asked to sign, date and time this consent 
form. You will also be asked for your date of birth, age, race, gender, ethnicity, sickle 
cell type (genotype).  You will also be asked your doctors names, about your medicines, 
and how many times you went to the emergency department and hospital in the last 
year.   You will be asked how long you went to school, if you are working and how much 
money you are making. You will be randomly assigned (like a coin toss) to receive care 
for your bad pain at your next emergency department visit using the patient-specific 
pain treatment or weight-based pain treatment. You have an equal chance of being in 
either group. Your hematologist/sickle cell care team will know which group you are in. 
At your next emergency department visit for bad sickle cell disease pain, you will be told 
what drug and what dose are ordered for you. You will not be told if you are in the 
patient-specific treatment or weight-based treatment.  You may or may not benefit by 
participating in this study.   
 
Emergency department care 
In the emergency department, you will be asked about your pain every 30 minutes. 
Additional medicines may be given as needed every 20-30 minutes. Medicines will 
include opioids (strong pain medicines that may be called narcotics), either morphine or 


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hydromorphone (also called Dilaudid). The medicines will be given intravenously (IV) or 
under the skin. These pain medicines may be given to you in higher doses than you 
would normally take, or more often. 
 
Pain management protocols  
Patient-specific protocol group 
If you are assigned to this group, members of your healthcare team will write a pain 
treatment plan just for you. The plan will be based on the pain medicines you take at 
home, and what was needed during your past hospital and emergency department visits 
to treat your pain. This plan will be used the next time you come to the emergency 
department for bad sickle cell disease pain. The plan will include the specific medicines, 
doses of those medicines, how often you should receive them and how you will receive 
them.  The plan will be written by your hematologist/sickle cell team and will be 
available to Emergency Medicine doctors.  
 
Weight-based protocol group 
If you are randomized to this group, members of your healthcare team will write a pain 
treatment plan just for you based on your weight. This plan will be used the next time 
you come to the emergency department for bad sickle cell disease pain. The plan will 
include the specific medicines and their doses. The plan will be written by your 
hematologist/sickle cell team and will be available to Emergency Medicine doctors. The 
first dose of pain medicine will be based on your weight.  
 
ED Visit Interviews: At the first emergency department visit for bad sickle cell disease 
pain, you will be asked questions about your pain and symptoms.  This will take about 5 
minutes. You will be asked again about every 30 minutes until you are admitted to the 
hospital, discharged home, transferred to observation status or for a maximum of 6 
hours, whichever comes first.  Research staff will also take your blood pressure (using a 
blood pressure cuff), check your oxygen saturation (by placing a probe on the outside of 
your finger) and measure your level of fatigue. 
 
When you leave the emergency department (whether you are discharged to home, 
transferred to a different hospital, or admitted to the hospital), you will be asked a few 
questions about how you feel about the pain treatment you received.  
 
Medical record review:  7 days after you leave the emergency department, research 
staff will review your chart and write down all medicines you received, and any follow-up 
emergency department visits or hospitalizations you may have had.  
 
Summary of the differences of being in this study compared to your usual care 
By participating in this research study, your pain management may be better than usual 
care because both treatment plans suggest giving medicines more often and at higher 
doses than what you may receive in many emergency departments.  


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HOW LONG WILL I BE IN THIS STUDY? 
Your participation will end after your next emergency department visit for bad sickle cell 
disease pain, up to 2 years, or until the study ends, whichever comes first. Participation 
in the study does not require you to come to the emergency department, it only decides 
how your pain will be managed if you come to the emergency department for treatment 
of bad sickle disease pain.  
 
You can choose to stop participating at any time without penalty or loss of any benefits 
to which you are otherwise entitled. However, if you decide to stop participating, we 
encourage you to talk to your doctor first. 
 
If you choose to stop participating, or after the study has been completed, the 
emergency department physician will treat your sickle cell pain as they usually do (usual 
care).  
 
WHAT ARE THE RISKS OF THE STUDY? 
As a result of your participation in this study, you are at risk for the following side 
effects. You should discuss these with the study doctor and your regular health care 
provider if you choose. 
 
Morphine Sulfate or Hydromorphone may cause some, all or none of the side-effects 
listed below. 
 
More likely  
 Drowsiness and sedation, preventing you from being alert or staying 
awake 
 Nausea, vomiting 
 Itching 
 Light-headedness 
 sedation  
 sweating/flushing 
 euphoria 
 dry mouth 
 
Less Likely  
  Respiratory depression (breathing is slowed or stops in severe cases) 
  Low blood pressure 
 apnea 
 circulatory depression 
 cardiac arrest 
 and shock 


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There is also the risk that participating in this research study may provide less pain 
control than you normally experience.  It is also possible that you may experience more 
side effects if you receive higher doses than you would normally receive using the pain 
treatment plans in this study. However, you will be carefully monitored to reduce these 
risks. To minimize side effects, the nurse and doctor in the emergency department will 
check your pain levels and any reaction to the pain medicines. In addition, the research 
assistant will check your blood pressure, pain and sleepiness levels, breathing and 
oxygen level about every 30 minutes. 
  
There is also a potential risk of loss of confidentiality.  Every effort will be made to keep 
your information confidential; however, this cannot be guaranteed.  You may refuse to 
answer any of the questions and you may take a break at any time during the study.  
You may choose to stop being a part of this study at any time.  
 
There may be risks, discomforts, drug interactions or side effects that are not yet 
known. 
 
WHAT IF I AM PREGNANT? 
Opioids are not associated with birth defects, but may cause the baby to move less and 
slow down his/her heart rate, however there may be unexpected risk. Opioids are often 
used to treat pregnant women with severe pain, including women with sickle cell 
disease. Treating your pain with opiates is recommended by the American College of 
Obstetricians and Gynecologists. You can participate in this study if you are pregnant. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
If you agree to take part in this study, it is possible that your pain may be managed 
better than if you were not part of this study.  Both the patient-specific and weight-based 
treatment plans may offer you better, or faster pain control than what you normally 
experience during an emergency department visit. If you are assigned to the patient-
specific treatment plan, you may receive better or faster pain relief compared to the 
weight-based treatment plan. The information learned from this study will benefit other 
individuals living with sickle cell pain who come to the emergency department for pain 
management.  
 
ARE THERE ALTERNATIVES TO TAKING PART IN THE STUDY? 
If you decide that you do not want to take part in this study, you will be treated 
according to usual care practices for patients with sickle cell disease pain.  These 
treatments may include opioids, such as morphine or hydromorphone (also known as 
Dilaudid), and other pain medicines such as ketorolac or ibuprofen. Please talk to your 
doctor about these and perhaps other options, and their risks and benefits. 
 


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WILL MY INFORMATION BE KEPT CONFIDENTIAL? 
Study records that identify you will be kept confidential as required by law. Federal 
Privacy Regulations provide safeguards for privacy, security, and authorized access. 
Except when required by law, you will not be identified by name, social security number, 
address, telephone number, or any other direct personal identifier in study records 
disclosed outside of the study site. The research team from Duke and the Duke Clinical 
Research Institute (DCRI) will have access to your study files and informed consent; 
they are required to review these documents to make sure your research site is 
complying with ethical practices. Your consents will stay at the study site. However, a 
copy of your signed consent form may be temporarily uploaded to a password-
protected, secure, encrypted cloud based system (Duke-Box) to allow the DCRI 
monitor(s) to review the signed form. As soon as the consent form is reviewed by the 
monitor, the form will be permanently deleted from the system. You will be assigned a 
unique code number. The key to the code will be kept on a secure computer network 
drive behind a password-protected firewall at the study site. Only study personnel at 
each respective study site, including the research assistants who will be conducting the 
interviews will have access to your personal identifier information. Duke will receive de-
identified information only via a web-based data system. No identifiable information will 
be included in the database. You have the right to access your own Personal Health 
Information (PHI) at any time. 
 
A Certificate of Confidentiality from the National Institutes of Health covers this 
research. The COMPARE_VOE researchers at Duke University may not share or use 
information that may identify you in any federal, state, or local civil, criminal, 
administrative, legislative, or other action, suit, or proceeding, or used as evidence 
without your consent to do so.  Information that might identify you cannot be shared with 
anyone who is not connected with the research unless there is a federal, state or local 
law that required sharing your information. An example that would require information 
that might identify you to be shared would be to report child abuse or communicable 
diseases. Information that could identify you can be shared if you have consented to 
share identifying information, including your medical treatment, or if your information is 
used for other scientific research, as allowed by federal regulations protecting research 
subjects. 
 
As part of the study, Dr. Tanabe, Dr. Barnhart, and their study team will report the 
results to the National Institutes of Health.  In addition, your records may be reviewed in 
order to meet federal or state regulations.  Reviewers may include representatives of 
the National Institutes of Health, <<CF-Main SMO Company 1>><<CF-Main Affiliated IN 
Language 1>>the United States Food and Drug Administration (FDA), the Institutional 
Review Board (IRB) that reviewed this research, or the Duke University Health System 
Institutional Review Board. If any of these groups review your research record, they 
may also need to review your entire medical record. 
 


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These people may look at your records to make sure the study has been done the right 
way.  They also want to make sure that your health information has been collected the 
right way, or for other reasons that are allowed under the law. 
 
The study results will be retained in your research record for at least six years after the 
study is completed.  At that time the research information not already in your medical 
record will be destroyed or information identifying you will be removed from such study 
results at Duke Clinical Research Institute.  Any research information in your medical 
record will be kept indefinitely. 
 
This information may be further disclosed by the sponsor of this study, National 
Institutes Health, or by outside reviewers for audit purposes.  If disclosed by the sponsor 
or outside reviewers, the information is no longer covered by the federal privacy 
regulations.   
 
While the information and data resulting from this study may be presented at scientific 
meetings or published in a scientific journal, your identity will not be revealed. 
 
WHAT ARE THE COSTS? 
There will be no additional costs to you as a result of being in this study beyond what 
you normally pay for an emergency department visit. You may talk to the study staff and 
your insurance company about what is covered. 
 
WHAT ABOUT COMPENSATION? 
If you have an emergency department visit for bad sickle cell disease pain during the 
study period, you will be compensated $XX.00. 
 
OR You will not receive any payment for taking part in this research study. 
 
<<CF-Main Payment for Part. Paragraph>> 
 
WHAT ABOUT RESEARCH RELATED INJURIES? 
If you are injured or get sick because of being in this research, call the study doctor 
immediately. The study doctor will provide medical treatment or refer you for treatment. 
Immediate necessary medical care will not be available at Duke University Medical 
Center in the event that you are injured as a result of your participation in this research 
study. There is no commitment by Duke University, Duke University Health System, 
Inc., to provide monetary compensation or free medical care to you in the event of a 
study-related injury. 
 
Immediate necessary medical care is available at the study site in the event that you are 
injured as a result of your participation in this research study. However, there is no 


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commitment of the study site physicians to provide monetary compensation or free 
medical care to you in the event of a study-related injury.   
 
For questions about the study or research-related injury, contact the study doctor. If you 
have other questions about the study, you can also contact Dr. Paula Tanabe (Duke 
University) at (919) 613-6038 during regular business hours and at (312) 502-0185 after 
hours and on weekends and holidays. 
 
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM 
THE STUDY? 
You may choose not to be in the study, or, if you agree to be in the study, you may 
withdraw from the study at any time. If you choose to withdraw during an emergency 
department visit, notify the doctor taking care of you. If you do decide to withdraw 
permanently (all future visits), we ask that you notify the study doctor.  
 
If you withdraw from the study, no new data about you will be collected for study 
purposes other than data needed to keep track of your withdrawal or if you have a side 
effect related to the study. All data that has already been collected for study purposes 
will be sent to the study sponsor (National Institutes of Health).   
 
Your decision not to participate or to withdraw from the study will not involve any penalty 
or loss of benefits to which you are otherwise entitled and will not affect your access to 
health care at the study site.   
 
We will tell you about new information that may affect your health, welfare, or 
willingness to stay in this study. 
 
Your doctor or the sponsor may decide to take you off this study if your condition gets 
worse, if you have serious side effects, or if your study doctor determines that it is no 
longer in your best interest to continue.  The sponsor or regulatory agencies (such as, 
the FDA) may stop this study at any time without your consent. Reasons why this might 
occur include stopping the study for safety reasons, the funding for the study runs out or 
the study has enrolled and treated enough patients to answer the research question.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about the study or a research-related injury, or if you have problems, 
concerns, complaints, questions or suggestions about the research, contact the 
research team at the phone number(s) listed above on the first page. Dr. Tanabe may 


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also be contacted at (919) 613-6038 during regular business hours and at (312) 502-
0185 after hours and on weekends and holidays. 
 
This research is being overseen by an Institutional Review Board (“IRB”). An IRB is a 
group of people who perform independent review of research studies. The goal of the 
IRB is to protect the rights and welfare of study subjects. You may talk to them at (888)-
303-2224 or (800) 562-4789, irb@cgirb.com if: 
 
 You have questions, concerns, or complaints that are not being answered by the 
research team. 
 You are not getting answers from the research team. 
 You cannot reach the research team. 
 You want to talk to someone else about the research. 
 You have questions about your rights as a research subject. 


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STATEMENT OF CONSENT 
"The purpose of this study, procedures to be followed, and the study’s risks and benefits 
have been explained to me. I have been allowed to ask questions, and my questions 
have been answered to my satisfaction. I have been told whom to contact if I have 
questions, to discuss problems, concerns, or suggestions related to the research, or to 
obtain information or offer input about the research. I have read this consent form and 
voluntarily agree to be in this study, with the understanding that I may withdraw at any 
time. I have been told that I will be given a signed and dated copy of this consent 
form<<CF-Main California Bill of Rights>>." 
 
 
________________________________________ 
___________     ___________ 
Signature of Subject 
 
 
 
 
Date  
      Time 
 
 
________________________________________ 
Printed Name of Subject 
 
 
 
 
  
 
 
________________________________________ 
___________     ___________ 
Signature of Person Obtaining Consent  
 
Date  
      Time 
 
 
__________________________________________ 
Printed Name of Person Obtaining Consent 


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HIPAA AUTHORIZATION 
 
Federal regulations give you certain rights related to your health 
information.  These include the right to know who will receive the 
information and how it will be used.  The study doctor must obtain your 
authorization (permission) to use or release any health information that 
might identify you. 
 
WHAT INFORMATION MAY BE USED AND SHARED? 
The study doctor and study staff will use and share your health information 
as part of this research study. Except when required by law, you will not be 
identified by name, address, telephone number or other facts that could 
identify the health information as yours.   
 
Examples of the information that may be used are: 
 
 Medical records (from any doctor, hospital or other healthcare 
provider) 
 Information created or collected during the research.  This could 
include your medical history, and dates or results from any physical 
exams, laboratory tests or other tests. 
 
WHO WILL RECEIVE INFORMATION ABOUT YOU? 
The study doctor and study staff will share your personal health information 
with: 
 
 the sponsor, including persons or companies working for or with the 
sponsor 
 Independent/Institutional Review Board (IRB) <<CF-Main SMO 
Company 2>><<CF-Main Affiliated IN Language 2>> 
 the U.S. Food and Drug Administration (FDA) 
 Department of Health and Human Services (DHHS) agencies 
 other regulatory agencies  
 
WHY WILL THIS INFORMATION BE USED AND/OR GIVEN TO 
OTHERS? 
The sponsor and the groups above will use your health information: 


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 to complete this research 
 to evaluate the results of the study 
 to check that the study is being done properly 
 to obtain marketing approval for new products resulting from this 
research 
 
IS MY HEALTH INFORMATION PROTECTED AFTER IT HAS BEEN 
GIVEN TO OTHERS? 
Your health information may be further shared by the groups above. If 
shared by them, the information will no longer be covered by this 
Authorization.  These groups are committed to keeping your health 
information confidential.  
 
WHAT IF I DECIDE NOT TO ALLOW THE USE OF MY HEALTH 
INFORMATION? 
You do not have to sign this form.  If you do not sign this form, you cannot 
take part in this research study.  
 
MAY I WITHDRAW OR REVOKE (CANCEL) MY PERMISSION? 
YES.  You may withdraw your permission to use and disclose your health 
information at any time.  You can do this by sending written notice to the 
study doctor.  If you withdraw your permission, you will not be able to 
continue being in the research study. 
 
WHAT HAPPENS IF I WANT TO WITHDRAW MY AUTHORIZATION? 
Information that has already been gathered may still be used and given to 
others.  If you withdraw your permission, no new health information will be 
gathered unless you have a side effect related to the study.   
 
If you withdraw from the study but do not withdraw your Authorization, new 
health information may be collected until this study ends.   
 
WILL MY AUTHORIZATION EXPIRE? 
If you do not withdraw this Authorization, it will remain in effect. 
 


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If the research site is located in California, Delaware, Indiana, Washington, 
or Wisconsin this authorization will expire on 31Dec2060. 
 
There is no expiration of this authorization except for research conducted in 
the states listed above. 
 
MAY I REVIEW OR COPY THE INFORMATION OBTAINED OR 
CREATED ABOUT ME? 
YES. You have the right to review and copy your health information.  
However, your access to this information may be delayed until the study is 
complete. 
 
Your decision to withdraw your Authorization or not to participate will not 
involve any penalty or loss of access to treatment or other benefits to which 
you are otherwise entitled.   
 


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AUTHORIZATION 
By signing this form, I allow the use or disclosure of my health information.  
I will receive a signed and dated copy of this Authorization. 
 
 
 
 
Printed Name of Subject 
 
 
 
 
Signature of Subject 
Date 
 

SAP_003.pdf: 
 
 
ITL 
TITLE PAGE 
 
 
 
 
Statistical Analysis Plan 
 
A Comparison of Individualized vs. Weight-Based Protocols to Treat  
Vaso-Occlusive Episodes in Sickle Cell Disease  
SHORT TITLE: COMPARE VOE 
 
 
Final Version 1.0 
Approval Date: 9/17/2019 
 
 
Funded by: Heart, Lung and Blood Institute, National Institutes of Health 
 
 
Principal Investigator(s): Paula Tanabe, Ph.D., RN, CCC PI, Laurel Chadwick Distinguished 
Professor, Associate Dean for Research Development and Data 
Science, School of Nursing, Duke University 
 
 
 
 
  
                                                  Huiman Barnhart, Ph.D., DCC PI, Professor, Department of  
                                                  Biostatistics and Bioinformatics, and Duke Clinical Research Institute  
                                                  (DCRI), Duke University 
 
Prepared by: Hongqiu Yang, Ph.D., Senior Biostatistician, Clinical Trials Statistics, DCRI 


 
1 
 
TABLE OF CONTENTS 
 
TITLE PAGE ...................................................................................................................................0 
PROTOCOL SYNOPSIS .............................................................................................................5 
ABBREVIATIONS .........................................................................................................................7 
1. 
INTRODUCTION ........................................................................................................9 
2. 
OVERVIEW OF TRIAL DESIGN ...........................................................................10 
2.1. 
Basic Study Design ..................................................................................................10 
2.2. 
Treatment Arms ........................................................................................................10 
2.3. 
Blinding ......................................................................................................................10 
2.4. 
Planned Sample Size ..............................................................................................10 
2.5. 
Randomization ..........................................................................................................11 
3. 
OVERVIEW OF ELIGIBILITY AND PROCEDURES .........................................12 
3.1. 
Eligibility Criteria .......................................................................................................12 
3.1.1. 
INCLUSION CRITERIA ............................................................................................12 
3.1.2. 
EXCLUSION CRITERIA ..........................................................................................12 
3.1.3. 
ENROLLMENT INCLUSION CRITERIA: ...............................................................12 
3.1.4. 
ENROLLMENT EXCLUSION CRITERIA..............................................................12 
3.2. 
Study Procedures / Blinding ...................................................................................12 
3.3. 
Schedule of Assessment (section 18) ..................................................................14 
4. 
ENDPOINTS .............................................................................................................15 
4.1. 
Primary Endpoint and Hypothesis .........................................................................15 
4.2. 
Secondary Endpoints ..............................................................................................17 
4.3. 
Exploratory Analysis of Safety Outcomes ............................................................17 
5. 
OVERVIEW OF REPORT ......................................................................................18 
5.1. 
Purpose of Report ....................................................................................................18 
5.2. 
Report Production ....................................................................................................18 
5.3. 
Abbreviated Report Outline ....................................................................................18 
5.4. 
Source of Data Included in Report ........................................................................18 
6. 
REPORT STRUCTURE ..........................................................................................19 
6.1. 
Treatment Labels .....................................................................................................19 
6.2. 
P-values .....................................................................................................................19 


 
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6.3. 
Graphical Conventions ............................................................................................19 
6.3.1. 
BAR CHARTS...........................................................................................................19 
6.3.2. 
BOX PLOTS ..............................................................................................................19 
6.3.3. 
SCATTER PLOTS ...................................................................................................19 
6.3.4. 
ANNOTATIONS .......................................................................................................20 
7. 
NOTES ON ANALYSES.........................................................................................21 
7.1. 
General Conventions ...............................................................................................21 
7.2. 
Patient Accountability ..............................................................................................21 
7.3.  
Baseline Characteristics .........................................................................................21 
7.4. 
Assessments at the ED Visit ..................................................................................21 
7.5. 
Dosing ........................................................................................................................21 
7.6.  
Safety Outcomes ......................................................................................................22 
7.7.  
Study Endpoints .......................................................................................................22 
7.7.1.  
PRIMARY ENDPOINT ............................................................................................22 
7.7.2.  
SECONDARY ENDPOINTS...................................................................................23 
7.8.  
Supporting Materials ................................................................................................23 
8.              PATIENT ACCOUNTABILITY ...............................................................................26 
8.1. 
Patient Accountability ..............................................................................................26 
8.2. 
Number of Subjects Randomized by Site ............................................................27 
8.3. 
Number of Subjects Enrolled by Site ....................................................................28 
9. 
BASELINE CHARACTERISTICS .........................................................................30 
9.1. 
Age by Treatment.....................................................................................................30 
9.2. 
Gender by Treatment ..............................................................................................30 
9.3. 
Race by Treatment ..................................................................................................31 
9.4. 
Medical History by Treatment ................................................................................31 
9.5. 
Prior History of Pain Medications by Treatment ..................................................32 
10. 
ASSESSMENTS ......................................................................................................34 
10.1. 
Pain Score Over Time - Every 30 minute.............................................................34 
10.2. 
Blood Pressure Over Time - Every 30 minute .....................................................34 
10.3. 
Heart Rate Over Time - Every 30 Minute .............................................................34 
10.4. 
 SpO2 Over Time - Every 30 Minute .....................................................................34 
10.5. 
Sedation Score Over Time - Every 30 Minute .....................................................34 


 
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10.6. 
Respiration Rate Over Time - Every 30 Minute ..................................................34 
11. 
ADVERSE AND SERIOUS ADVERSE EVENTS...............................................37 
11.1. 
Protocol-Specific Expected Adverse Events .......................................................37 
11.2. 
Protocol-Specific Expected Serious Adverse Events .........................................38 
11.3. 
Severity of Expected Serious Adverse Events ....................................................39 
12. 
ENDPOINTS .............................................................................................................41 
12.1. 
Primary Endpoint - Reduction of Pain Score by Treatment – Adjusted ..........41 
12.2. 
Primary Endpoint - Reduction of Pain Score by Treatment – 
Unadjusted ................................................................................................................41 
12.3. 
Subgroup Analyses of the Primary Endpoint .......................................................42 
12.4. 
Secondary Endpoint – Length of Index ED Stay (hr.) – Descriptive ................43 
12.5. 
Hospitalization for Pain Control – Descriptive .....................................................44 
12.6. 
Return ED Revisits...................................................................................................44 
12.7. 
Hospitalizations (if not admitted to hospital on Index ED visit) .........................45 
12.8. 
Re-hospitalizations (if admitted to hospital on Index ED visit, but 
discharged) ...............................................................................................................45 
12.9. 
Day Hospital Visits ...................................................................................................46 
12.10. 
ED Revisits or Hospital Re-admissions or Day Hospital Visits Within 7 
Days After Index ED visit (Binary Outcome with A Cutoff at Zero) ..................46 
12.11. 
Number of ED Revisits or Hospital Re-admissions or Day Hospital 
Visits Within 7 Days After Index ED visit ..............................................................47 
13. 
BASELINE CHARACTERISTICS (TABLES) .....................................................49 
13.1. 
Baseline Characteristics and Medical History .....................................................49 
13.2. 
Prior History of Pain Medications by Treatment ..................................................51 
14. 
 ADVERSE AND SERIOUS ADVERSE EVENTS (TABLES) ..........................52 
14.1. 
Adverse Events ........................................................................................................52 
14.2. 
Serious Adverse Events ..........................................................................................53 
15. 
HOSPITALIZATION (TABLE) ...............................................................................54 
15.1.          Hospitalization..........................................................................................................54 
16.                  ASSESSMENTS AT ED VISIT (TABLE) ............................................................55 
16.1.           Assessments ...........................................................................................................55 
17.                 STUDY ENDPOINTS (TABLE) .............................................................................58 
17.1.          Endpoints ..................................................................................................................58 
17.2.          Endpoints (Sensitivity Analyses) ...........................................................................58 


 
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17.3.        Subgroup Analysis of the Primary Endpoint .........................................................59 
 
 
 


 
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PROTOCOL SYNOPSIS 
 
Title: 
A Comparison of Individualized vs. Weight Based Protocols To 
Treat Vaso-Occlusive Episodes (VOE) in Sickle Cell Disease (SCD)  
Short Title 
COMPARE-VOE 
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 
Regimen 
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. 
Blinding 
The provider is unblinded in the ED.  The patient and research 
assistants are blinded to study arm. 
Objectives: 
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. 
 
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, if not admitted to hospital on ED visits 
• Re-hospitalizations, if admitted to hospital on ED visit and was 
discharged – we ignore those still hospitalized within 7 days of 
the index ED visits 
• Day hospital visits, regardless admitted to hospital on ED visits 
or not 
• A composite of return ED revisits or hospital re-admissions or 
day hospital visits (binary outcome with a cutoff at zero) 
 


 
6 
 
Location: 
6 clinical sites (Emergency Departments (ED)) in the United States 
Duration of 
Treatment 
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. 
 
Duration of Study 
Overall 
The study duration is from the time of placement in a treatment area 
to Day 7 Post ED Visit.  The study enrollment is expected to be 24 
months. 
 


 
7 
 
ABBREVIATIONS 
 
ACS 
Acute Chest Syndrome 
ACEP 
American College of Emergency Physicians 
AE 
Adverse Event 
CCC 
Clinical Coordinating Center 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
ED 
Emergency Department 
EDC 
Electronic Data Capture 
EMR 
Electronic Medical Record 
ITT 
Intent To Treat 
KG 
Kilogram 
NHLBI 
National Heart, Lung and Blood Institute 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCD 
Sickle Cell Disease 
SD 
Standard Deviation  
SpO2 
Peripheral Saturation of Oxygen 
VOE 
Vaso-Occlusive Episode 
 
 
 


 
8 
 
 
 
 
 
 
 
 
 
Part I 
 
Introduction 


 
9 
 
1. 
INTRODUCTION 
 
This document is the statistical analysis plan (SAP) describing data summaries and 
analyses for the final report of this study, a comparison of individualized vs. weight-
based protocols to treat vaso-occlusive episodes in sickle cell disease. Production of 
data summaries and analyses described in this SAP will be the responsibility of the 
Data Coordinating Center (DCC). 
 
The reader of this Statistical Analysis Plan is encouraged to refer to the study protocol 
for details on the conduct of this study, the operational aspects of clinical assessments, 
and the timing for completing the participation of a patient in this study. This Statistical 
Analysis Plan is intended to provide guidance to the generation and presentation of the 
final statistical report.   


 
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2. 
OVERVIEW OF TRIAL DESIGN 
 
This section summarizes the basic trial design, treatment arms, blinding, planned 
sample size, and randomization scheme.   
 
2.1. 
Basic Study Design 
 
A multi-site Phase III, single blinded, randomized clinicial trial 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 (from 
Section 4 of the protocol).  The modified intent to treat (ITT) population is adult SCD 
patients with an ED visit due to VOE.  
 
2.2. 
Treatment Arms 
 
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. (section 6 of the protocol) 
 
2.3. 
Blinding 
 
The patient hematologist  will be un-blinded to the analgesic protocol and will write the 
treatment plan based on the randomized assigned analgesic protocol to be uploaded in 
uploaded to the electronic medical record (EMR).  However, the emergency physician 
will be 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. (section 6) 
 
2.4. 
Planned Sample Size 
 
A sample size of 230 subjects with ED visits provides 90% power to detect a 14-mm 
clinically significant reduction in pain scores for the patient-specific analgesic protocol 
versus the weight-based analgesic protocol with a 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% 


 
11 
 
missing data rate.  (section 13) 
 
 
2.5. 
Randomization 
 
After patients have provided informed written consent, they will be randomized to either 
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. (section 8) 
 
 


 
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3. 
OVERVIEW OF ELIGIBILITY AND PROCEDURES 
 
This section summarizes eligibility criteria, study procedures, dosing regimen and visit 
schedule. (section 5) 
 
3.1. 
Eligibility Criteria 
 
The population eligible for randomization consists of adult SCD patients meeting 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.   
 
3.1.1. 
Inclusion Criteria  
1) > 18 years of age 
2) SCD patients with the following genotypes: 
a. Hgb SS, SC and SB+, SB- thalassemia 
3.1.2. 
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 
 
The enrolled population will consist of eligible patients meeting the following criteria. 
 
3.1.3. 
Enrollment Inclusion Criteria:  
1) Patient is randomized 
2) ED visit for VOE requiring parenteral opioid analgesia 
 
3.1.4. 
Enrollment Exclusion Criteria 
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 
 
3.2. 
Study Procedures / Blinding 
 
When the randomized patient has an ED visit for VOE, this patient is enrolled in the 


 
13 
 
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 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 and 7-day post ED data are extracted from medical records. 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. (section 9 of the protocol) 
 
 


 
14 
 
 
3.3. 
Schedule of Assessment (section 18) 
 
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 
  
 
 
 
 
 
 
 
 


 
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4. 
ENDPOINTS 
4.1. 
Primary Endpoint and Hypothesis 
 
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.  
 
The Primary Hypothesis of the study population is that the patient-specific analgesic 
protocol is superior to the weight-based analgesic protocol. (section 11 of the protocol).  
The sample size of 230 subjects with ED visits provides 90% power to detect 14-mm 
clinically significant assumptions of the same standard deviations (SD) of 31 mm in pain 
score reductions in the two groups while accounting for 10% missing data rate. 
 
Method of the Final Analysis will be linear regression used to test the primary 
hypothesis with pain score reduction (0-100mm) as the dependent variable and 
treatment indicator with pain score at arrival, biological variables of SCD genotype, age 
and gender as covariates (independent variables).  The primary analysis for hypothesis-
testing will be done on the observed data without imputation and without regard to the 
proportion of missing cases.  Summaries of the p-value, 95% confidence intervals and 
the difference in outcome between the two arms, as well as outcome in each arm will 
also be computed and presented in tabular and graphic format. 
Details will be presented later (section 7 of the SAP). 
Missing Data and Sensitivity Analyses of the Primary Endpoint: If more than 5% of 
randomized patients have the pain score reduction missing, we will use multiple 
imputations in a sensitivity analysis, which would be considered supportive if it gave 
results consistent in direction and magnitude with the primary analysis. Highly 
inconsistent results would require further review of how and why the data were missing 
and suggest concerns with study conduct. 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. In another potential sensitivity analysis, we 
will also 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. (section 13.8. of the protocol) 
 


 
16 
 
If fewer than 5% of patients have a missing arrival or discharge pain score evaluation, 
we will perform the primary analysis on the patients without missing data.  Two 
sensitivity analyses will be done:   
1.) Worst case, assuming missing discharge pain scores are 0 in the weight-based 
arm and 100 in the patient-specific arm.  Missing arrival scores will be assigned 
the mean of the study population arrival scores. 
2.) LOCF – imputing missing discharge scores as the last score recorded on the Q 
30-minute assessment prior to discharge. Missing arrival scores will be assumed 
to take the value of the first score recorded on the Q 30-minute assessment.  
{Although LOCF is in general not a recommended technique, it could be 
informative in this situation.}   The missingness would be due to lack of 
assessment resulting from one of the four reasons below, each of which could be 
informed by the most recent pain score. 
i. The patient is discharged home    
ii. The patient is admitted to the hospital 
iii. The patient is assigned to observation status for continued pain 
management   
iv. The patient has received 6 hours of treatment 
 
The best approach to missing data is to obtain complete data collection.  Age, gender, 
and SCD type should be available for all patients.  SCD type should be one of:  Hgb SS,  
SC, or SB+, SB0 thalassemia.  .   
The trial will be closely monitored for missing time of bed placement or missing 
discharge, or 6 hours, pain scores.  The first occurrence of missingness within a center 
will require explanation from the center and a plan to avoid missing data in subsequent 
patients.   
For patients with dosing deviations, we plan to include them in the primary intent-to-treat 
analysis and collect all study measurements as planned.  
Subgroup Analysis of the Primary Endpoint  
We will examine whether the finding for the primary endpoint is similar for all patients, 
or whether it varies according to the following pre-specified subgroups. These will be 
assessed via interaction terms between treatment and subgroup categories tested at 
nominal 0.10 level.   
 
1) Clinical site 
2) Gender 
3) Age (< 30, ≥ 30 years old) 
4) Genotypes (Hgb SS + SB0 and SC + SB+) 
5) Route (IV or SC) - this will not be carried out if 90% or more subjects receive the IV 
route. 
6) Use (yes/no) of NSAIDS 
7) Drug administered 
8) Number of repeated doses 


 
17 
 
9) Total administered milligrams of drug 
 
These analyses will utilize the regression models with main effects and interactions 
between the randomized groups and pre-specified subgroup variables.   
 
Details of presentation of results are illustrated in section 7. 
 
4.2. 
Secondary Endpoints 
 
The secondary endpoints are as follows:  
•  ED length of stay  
•  Hospitalization for pain control 
• Return ED visits 
• Hospitalizations, if not admitted to hospital on ED visits 
• Re-hospitalizations, if admitted to hospital on ED visit and was discharged – we 
ignore those still hospitalized within 7 days of the index ED visits 
• Day hospital visits, regardless admitted to hospital on ED visits or not 
• A composite of return ED revisits or hospital re-admissions or day hospital visits 
(binary outcome with a cutoff at zero) 
 
Methods of the final analyses: For the ED length of stay (from ED admission 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 or re-hospitalizations, or day 
hospital visits 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. (section 13.9.) 
 
4.3. 
Exploratory Analysis of 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. 


 
18 
 
5. 
OVERVIEW OF REPORT 
 
This final report will be prepared by the Data Coordinating Center (DCC) and be used 
for the publication of study results. 
 
The final report will summarize data and provide results of endpoints by treatment arm.  
All the calculations for the interim analyses will also be incorporated into the final 
analysis. These results will be intended for use by the Sponsor and other parties 
involved in the conduct of the study at the discretion of the Sponsor. 
5.1. 
Purpose of Report 
 
The primary purpose of the final report is to summarize selected baseline 
characteristics, adverse events, laboratory assessments, other safety measures, and 
results of study endpoints based on the final data. The final report will be based on 
modified intent-to-treat population only, and will include screening and baseline 
information on such subjects.  
5.2. 
Report Production 
 
 
SAS version 9.4 or later will be used to perform the analyses and create the graphics 
and tables for the report. 
5.3. 
Abbreviated Report Outline 
 
This report contains the following sections and chapters: 
 
• Introduction 
• Main Material 
– Patient Accountability 
– Baseline Characteristics 
– Assessments at the ED Visit 
– Adverse and Serious Adverse Events 
– Study Endpoints 
• Supporting Material 
This section will provide the same content as in the Main Materials, but in a tabular 
format with more numeric details. 
 
5.4. 
Source of Data Included in Report 
Study data will be collected through a customized web-based electronic data capture 
(EDC) system. The system that will be used is the Merge Healthcare’s eClinical OS 
(eCOS), which has features that enable 21 CFR Part 11 compliance. eCOS is a flexible 
system for capturing, managing and reporting clinical research data in Phase I–IV 
studies. Randomization activities will also be conducted within the eCOS system at the 
DCRI. 


 
19 
 
6. 
REPORT STRUCTURE 
 
6.1. 
Treatment Labels 
 
Tables and figures will be grouped by treatment arms and total. 
 
6.2. 
P-values 
 
Except for the primary, secondary endpoints and safety outcomes for which we pre-
specified methods to use in section 4, P-values, where applicable, for continuous or 
ordered categorical data are computed using the nonparametric Kruskal-Wallis test. 
This test is appropriate for data with non-normal distributions and has power near that of 
the Student’s t-test when the data are normal. Pearson’s chi-square or Fisher exact is 
used for dichotomous (e.g., gender) and unordered (e.g., race) categorical data. The 
log-rank test is used to obtain p-values for time-to-event endpoints. Cox modeling will 
be used for time-to-event outcomes if there are covariates, such as the initial pain score 
at ED arrival, biological variables of SCD genotype, age and gender. 
 
6.3. 
Graphical Conventions 
 
6.3.1. 
Bar Charts 
 
Bar charts indicate for categorical data the number or percent of subjects by category. 
They are used to display a single categorical variable with mutually exclusive 
categories. Bar charts of related dichotomous variables are sometimes grouped 
together to form a multiple bar chart. A more detailed bar chart is used to display 
categorical data which has additional ordered subdivisions, as in the display of lab tests. 
 
6.3.2. 
Box Plots 
 
Boxplots indicate the distribution of continuous data based on percentiles (for example, 
the display for age and change from baseline). The top and bottom edges of the box 
represent the 25th and 75th percentiles of the data. The 5th and 95th percentiles are 
represented by the “whiskers” extending from the top and bottom of the box. The 
plotting symbol inside the box represents the median of the data. 
 
Change from baseline. For variables which are measured at several fixed time points, 
change from baseline is usually provided for the observed data. For continuous 
variables, change can be given either in the original units or as percent change. 
For dichotomous variables, change from baseline can be indicated by displaying follow-
up data separately for each baseline group. 
 
6.3.3. 
Scatter Plots 
 
For correlations of two continuous variables, scatter plots are used.   
 


 
20 
 
 
6.3.4. 
Annotations 
 
Figures indicate the number of subjects used for the analysis, under 
the corresponding portion of the plot. P-values corresponding to the comparisons of the 
treatment groups are included, where applicable. Figures are also annotated with the 
data source. 
 
 


 
21 
 
7. 
NOTES ON ANALYSES  
 
This section of the report Introduction contains additional details about analysis 
conventions and the contents of specific chapters. 
 
7.1. 
General Conventions 
 
The study population:  The ITT population will consist of all patients randomized.   
The modified ITT population will consist of randomized adult SCD patients with an ED 
visit due to VOE.  Summary of baseline characteristics and analysis of the primary 
endpoint will be done using the modified ITT population. The safety population will 
consist of all patients in the modified ITT population for whom the AE CRF is completed.  
Summaries of AE and SAE will be done using the safety population. 
Treatment A and B will be replaced with actual treatment names after the database 
lock and study’s unblinding. Baseline records are defined as those before the time of 
placement in treatment area of ED. Denominators will be the number of non-missing 
values of the variable in the analysis.  
 
7.2. 
Patient Accountability 
 
This section will describe patient accountability, overall and by treatment.  Bar charts 
will be used for the presentation. 
 
7.3.  
Baseline Characteristics 
 
This report displays treatment group comparisons for baseline variables including 
medical history and socio-demographic information.  Bar charts for categorical variables 
and boxplots for continuous variables will be used for the presentation of baseline 
characteristics. 
7.4. 
Assessments at the ED Visit    
This section will include a scatterplot of pain assessment results at the ED Visit from ED 
bed placement to reach time point of every 30 minute over time, overall and by 
treatment.  It will also include bar charts per question over time, regarding pain relief, 
change in pain, and pain medicine.  Bar charts in the same format will be displayed for 
nausea, vomiting, and pruritus, including results at ED bed placement.  Box plots of 
blood pressure, heart rate, SpO2, sedation score, and respiration rate will also be 
presented, including results at ED bed placement. 
 
7.5. 
Dosing 
 
We will present the percentage of agreement between the initial dose assigned and 
administered dose in a table format. 
 


 
22 
 
We will describe overall analgesic dosing by calculating descriptive statistics for the 
cumulative morphine equivalent dose delivered ( total mg, total mg/hr, total mg/kg, and 
mg/kg/hr), where hr is the number of hours from ED arrival to discharge.   
 
 Adjustments of analgesic dose and regimen subsequent to the initial dose are 
determined by the SCD provider’s current observation of the patient.  As the CRF does 
not capture all of the information available to the SCD provider, post hoc analysis of 
adherence to the dose adjustment plan from study data is challenging.   
 
7.6.  
Safety Outcomes 
This section contains bar chart displays of protocol-specific expected adverse event 
(AE) data, such as nausea, vomiting, puritis, SPO2 < 95% requiring supplemental 
oxygen via nasal cannula due to opiod therapy, moderate to severe sedation, 
drowsiness, respiratory depression not requiring intubation, and low blood pressure.   
 
This section also contains bar chart displays of the incidence of protocol-specific serious 
adverse events (SAE), including respiratory depression requiring naloxone 
administration given within the 2 hours of last administration of pain protocol drug, any 
event resulting in death, any event that is considered a life-threatening complication, 
any event requiring admission to the intensive care unit (ICU), any event requiring 
intubation, and hospitalizations with the primary reasons.      
 
 
7.7.  
Study Endpoints 
 
7.7.1.  
Primary Endpoint 
 
As defined in the protocol, the primary endpoint is “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.”  Comparison of mean changes in pain scores and the 
difference between treatment arms will be done using linear regression, adjusting for 
the initial pain score at ED arrival, biological variables of SCD genotype, age and 
gender. Comparison of unadjusted means will also be done using a t-test. P-value, 95% 
confidence intervals and the mean difference will be displayed in tabular format. The 
predicted values will be displayed in a scatter plot by treatment.  
 
Descriptive statistics such as n, mean, standard deviation (SD), median, 25th and 75th 
percentiles will be also presented for the primary endpoint. 
 
For subgroup analysis of the primary endpoint, in addition to the formal assessment of 
randomized group by covariate interactions as described in section 4, effects of the 
treatments will be calculated and displayed (with 95% CI and p-values) for the pre-
specified subgroups of patients in both tabular and graphic format.  These descriptive 
summaries will be carefully interpreted in conjunction with the formal interaction tests.   
 
Please refer to section 4 for methods of analysis. 


 
23 
 
 
 
 
7.7.2.  
Secondary Endpoints 
 
P-value and descriptive statistics such as n, mean, standard deviation (SD), median, 
25th and 75th percentiles and boxplots of summary statistics will be presented for ED 
length of stay.   
P-values, frequencies and percentages by treatment arm will be displayed for 
hospitalizations for pain control and counts of the return ED visits, hospitalizations, re-
hospitalizations, or day hospital visits within seven days of the index ED visit (recorded 
ED visit).  Return ED visits, hospitalizations, re-hospitalizations, or day hospital visits will 
also be evaluated by collapsing the data into a binary outcome with a cut off at zero 
after the index ED visit.  Bar charts will be used to compare the hospital admission or 
ED re-admission rates between the two groups.  For each patient, the hospitalization 
rate in the 7-day period following discharge from the ED will be categorized as 0, 1, or 
2+.  Hospitalization for patients who proceed directly from ED discharge to the hospital 
will be counted as the first admission/ readmission. 
7.8.  Supporting Materials 
 
Part III, Supporting Material, contains back-up tables of univariate statistics and detailed 
frequency counts for the graphical displays of the previous chapters. These tables are 
cross-referenced to and from the corresponding graphical pages. 
 
 


 
24 
 
 
 
 
 
Part II 
 
Main Material 
 
(supporting tables with numeric details  
are presented in Appendix A.2 ) 
 
 


 
25 
 
 
 
Chapter 1 
 
Patient Accountability 
 


 
26 
 
8. PATIENT ACCOUNTABILITY 
8.1. 
Patient Accountability  
 
 Screened 
 N = 
Eligible  
 N =  
Not Eligible 
N =  
Randomized 
 N =  
Arm A 
N = 
Enrolled 
N =  
Bed Placement 
Assessment 
N (%) =  
ED Disposition 
 N (%) =  
Completed Study and 
Medical Record Review 
N (%) =  
 Early Termination                 =N (%) 
       Change in Eligibility               =N 
       Withdrawal of Consent        =N 
       Investigator’s Decision         =N 
       Died                                          =N 
      No Index ED                             =N     
Enrolled 
N =  
Arm B 
N = 
Bed Placement 
Assessment 
N (%)   
ED Disposition 
N (%) =  
Completed Study and 
Medical Record Review 
N (%) =  
 Early Termination                 =N (%) 
       Change in Eligibility               =N 
       Withdrawal of Consent         =N 
       Investigator’s Decision          =N 
       Died                                           =N 
           No Index ED                            =N      
No ED / Ineligible 
N =
No ED / Ineligible 
N =  


 
27 
 
 
 
 
8.2. 
Number of Subjects Randomized by Site 
 
 
 
 
 
 
 
 
65
70
75
80
80
90
460
0
100
200
300
400
500
Site 3
Site 4
Site 1
Site 6
Site 2
Site 5
Total
Number of Subjects Randomized


 
28 
 
8.3. 
Number of Subjects Enrolled by Site 
 
 
 
 
 
 
 
32
35
38
40
40
45
230
0
50
100
150
200
250
Site 3
Site 4
Site 1
Site 6
Site 2
Site 5
Total
Number of Subjects Enrolled


 
29 
 
 
 
Chapter 2 
 
Baseline Characteristics 
 
 


 
30 
 
9. 
BASELINE CHARACTERISTICS 
 
 
9.1. 
Age by Treatment 
 
 
 
9.2. 
Gender by Treatment 
 
 
 
56%
44%
59%
41%
0
10
20
30
40
50
60
70
Male
Female
A   N=115
B   N=115


 
31 
 
9.3. 
      Race by Treatment 
 
 
 
 
9.4. 
Medical History by Treatment 
 
 
 
 
 
9.5%
66.5%
18.8%
5.2%
8.3%
70.3%
15%
6.5%
0
10
20
30
40
50
60
70
80
Black
White
Asian
Others
A   N=115
B   N=115
3.0%
4.5%
7.5%
8.9%
8.5%
9.5%
11.5%
12.5%
13.5%
15.5%
17.7%
23.5%
2.5%
5.4%
6.5%
8.5%
9.5%
10.3%
10.5%
10.5%
12.1%
14.5%
16.8%
20.2%
0.0%
5.0% 10.0% 15.0% 20.0% 25.0%
Seizure
Gallbladder Disease
Heart Failure
Kidney Dysfunction
TIA
Avascular Necrosis
Stroke
Reinopathy
Acute Chest Syndrome
Other
Pulmonary Hypertension
Leg Ulcers
% of Subjects
A
N=115


 
32 
 
9.5. 
Prior History of Pain Medications by Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
3.0%
4.5%
7.5%
12.9%
10.90%
8.5%
9.5%
11.5%
12.5%
15.5%
16.50%
28.5%
35.5%
34.1%
2.5%
5.4%
6.5%
8.5%
8.90%
9.5%
10.3%
10.5%
10.5%
14.5%
15.50%
29.9%
30.5%
36.3%
0.0% 5.0% 10.0%15.0%20.0%25.0%30.0%35.0%40.0%
Codeine
Ocycodone/Acetaminophen
Oxycodone
Hydrocodone
Fentanyl
Morphine
Hydrocodone/Acetaminophen
Naproxyn
Oxymorphone
Tramadol
Tramadol/Acetaminophen
Hydromorphone
Ibuprofen
Hydrocodone/Ibuprofen
% of Subjects
A   N=115
B   N=115


 
33 
 
 
 
 
 
Chapter 3 
 
Assessments at the ED Visit 
 
 


 
34 
 
10. 
ASSESSMENTS 
 
 
10.1.      Pain Score Over Time - Every 30 minute   
     (Figure to be created as example below) 
 
 
10.2.      Blood Pressure Over Time - Every 30 minute  
                (Figure to be created as example below) 
 
 
10.3. 
Heart Rate Over Time - Every 30 Minute   
                (Figure to be created as example below) 
 
 
10.4.       SpO2 Over Time - Every 30 Minute  
                (Figure to be created as example below) 
 
10.5. 
Sedation Score Over Time - Every 30 Minute  
                (Figure to be created as example below) 
 
10.6. 
Respiration Rate Over Time - Every 30 Minute  
                (Figure to be created as example below) 
 
 
 
 
 
 
 
 
 
 
 
 


 
35 
 
 
 
 
 
Example 
 
(Note: this is only an example/template for our study.  It does not 
indicate the time range or numbers from our study) 
 
 
 
 
 


 
36 
 
 
 
 
Chapter 4 
 
Adverse and Serious Adverse Events 
 
 
 
 


 
37 
 
11. 
Adverse and Serious Adverse Events 
 
11.1.      Protocol-Specific Expected Adverse Events 
 
 
3.0%
4.5%
7.5%
12.9%
8.5%
9.5%
11.5%
12.5%
15.5%
28.5%
35.5%
34.1%
2.5%
5.4%
6.5%
8.5%
9.5%
10.3%
10.5%
10.5%
14.5%
29.9%
30.5%
36.3%
0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0% 35.0% 40.0%
Pruritis
Gallbladder Disease
Leg Ulcers
SPO2 < 95%
Low Blood Pressure
Moderate to Severe Sedation
Vomiting
Reinopathy
Other
Respiratory Depression
Nausea
Drowsiness
% of Subjects
A   N=115
B   N=115


 
38 
 
 
11.2. 
Protocol-Specific Expected Serious Adverse Events 
 
 
 
 
0.3%
0.8%
2.6%
2.6%
3.0%
4.8%
0.2%
1.5%
2.3%
2.4%
2.5%
5.2%
0.0%
1.0%
2.0%
3.0%
4.0%
5.0%
6.0%
Life Threatening Complication
Any Event Resulting in Death
Event Requiring Incubation
Other
Respiratory Depression
Event Requiring Admission to ICU
% of Subjects
A   N=115
B   N=115


 
39 
 
11.3. 
Severity of Expected Serious Adverse Events 
 
 
 
 
 
 
 
1.2%
1.5%
1.3%
1.4%
1.5%
2.2%
1.1%
1.0%
1.4%
1.3%
1.7%
2.3%
1.3%
1.8%
2.6%
2.6%
3.0%
4.8%
1.2%
1.7%
2.5%
2.4%
3.1%
5.4%
0.4%
0.5%
0.4%
0.5%
3.5%
3.6%
4.0%
4.1%
5.1%
5.2%
5.5%
5.6%
Life Threatening Complication   B
                                                          A
Event Resulting in Death    B
                                                A
Event Requiring Incubation   B
                                                    A
Other   B
             A
Respiratory Depression   B
                                             A
Event Requiring ICU Admission   B
                                                           A
% of Subjects
Severe
Moderate
Mild


 
40 
 
 
 
 
Chapter 5 
 
Study Endpoints 
 
 
 


 
41 
 
12. 
ENDPOINTS 
(Note: Additional numbers and details will be presented in Part III in tabular 
format) 
 
12.1. Primary Endpoint - Reduction of Pain Score by Treatment – Adjusted  
 
 
Note: In this figure, reduction of pain score is calculated as pain score at time of  
placement in treatment area minus pain score at time of disposition 
 
 
12.2. 
Primary Endpoint - Reduction of Pain Score by Treatment – Unadjusted  
 
 
 
Note: In this figure, reduction of pain score is calculated as pain score at time of  
placement in treatment area minus pain score at time of disposition 
 
 
90
75
45
30
15
12
0
10
20
30
40
50
60
70
80
90
100
A = 115
B = 115
Reduction of Pain Score*
P-value=0.03
Upper CI
Estimate
Lower CI
90
75
45
30
15
12
0
10
20
30
40
50
60
70
80
90
100
A = 115
B = 115
Reduction of Pain Score*
P-value=0.03
Upper CI
Estimate
Lower CI


 
42 
 
12.3. 
Subgroup Analyses of the Primary Endpoint  
 
(Note: this is only an example/template for our study.  It does not indicate the 
time range or numbers from our study) 
 
 
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
43 
 
12.4. 
Secondary Endpoint – Length of Index ED Stay (hr.) – Descriptive 
 
 
 
Note: length of ED stay refers to the period from ED admission to the end of ED visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
90
75
45
30
15
12
0
10
20
30
40
50
60
70
80
90
100
A = 115
B = 115
Length of Hospital Stay (hr.)
P-value=0.03
Upper CI
Estimate
Lower CI


 
44 
 
 
12.5. 
Hospitalization for Pain Control – Descriptive 
 
 
 
 
 
12.6. 
Return ED Revisits 
 
 
 
 
 
56%
44%
59%
41%
0
10
20
30
40
50
60
70
No
Yes
A   N=115
B   N=115
56%
44%
59%
41%
0
10
20
30
40
50
60
70
No
Yes
A   N=115
B   N=115


 
45 
 
 
12.7. 
Hospitalizations (if not admitted to hospital on Index ED visit) 
 
 
 
 
 
12.8. 
Re-hospitalizations (if admitted to hospital on Index ED visit, but 
discharged) 
 
 
 
 
56%
44%
59%
41%
0
10
20
30
40
50
60
70
No
Yes
A   N=115
B   N=115
56%
44%
59%
41%
0
10
20
30
40
50
60
70
No
Yes
A   N=115
B   N=115


 
46 
 
 
 
12.9. 
Day Hospital Visits 
 
 
 
 
 
12.10. 
ED Revisits or Hospital Re-admissions or Day Hospital Visits Within 7 
Days After Index ED visit (Binary Outcome with A Cutoff at Zero) 
 
 
 
 
56%
44%
59%
41%
0
10
20
30
40
50
60
70
No
Yes
A   N=115
B   N=115
56%
44%
59%
41%
0
10
20
30
40
50
60
70
No
Yes
A   N=115
B   N=115


 
47 
 
 
 
12.11. 
Number of ED Revisits or Hospital Re-admissions or Day Hospital Visits 
Within 7 Days After Index ED visit  
 
 
 
 
 
 
90
75
45
30
15
12
0
10
20
30
40
50
60
70
80
90
100
A = 115
B = 115
Number of ED Revisits or Hospital Re-admissions
P-value=0.03
Upper CI
Estimate
Lower CI


 
48 
 
 
 
 
Appendix A. 2 
 
Supporting Materials 
 
 


 
49 
 
13. 
BASELINE CHARACTERISTICS (TABLES) 
 
13.1. 
Baseline Characteristics and Medical History 
 
 
 
Treatment A 
                 
N= 
 
Treatment B 
 
N= 
 
Total 
 
N= 
Age 
 
 
 
 
Genotypes 
   SS + SB- 
   SC + SB+ 
    
 
 
 
 
Gender 
      Male 
      Female 
      Refused 
      Don’t Know 
  
 
 
 
 
Ethnicity 
       Hispanic 
       Not-Hispanic or Latino 
       Refused 
       Don’t know 
 
 
 
 
 
Race 
 
 
 
   African American/Black 
 
 
 
   American Indian/Alaskan Native 
 
 
 
   Asian 
 
 
 
   Caucasian/White 
 
 
 
   Native Hawaiian/Pacific Islander 
 
 
 
   More than One 
 
 
 
   Other 
 
 
 
    Refused 
 
 
 
    Don’t Know 
 
 
 
Weight (kg) 
 
 
 
Acute chest syndrome 
 
 
 


 
50 
 
Stroke 
 
 
 
Seizure 
 
 
 
TIA (transient ischemic attack) 
 
 
 
Avascular necrosis of the hips or 
shoulders 
 
 
 
Pulmonary hypertension 
 
 
 
Heart Failure 
 
 
 
Kidney dysfunction 
 
 
 
Liver dysfunction 
 
 
 
Retinopathy 
 
 
 
Leg ulcers 
 
 
 
Gallbladder disease 
 
 
 
Other 
 
 
 
NSAID 
 
   Each Day: 
   Ibuprofen 
   Naproxyn 
 
    Day with Severe Pain: 
    Ibuprofen 
    Naproxyn 
 
 
 
 
 
 
 
 


 
51 
 
 
13.2. 
Prior History of Pain Medications by Treatment 
 
 
 
 
Treatment A 
                 
N= 
 
Treatment B 
 
N= 
 
Total 
 
N= 
Codeine 
 
 
 
Hydrocodone 
 
 
 
Hydrocodone/ 
   acetaminophen** 
 
 
 
Hydrocodone / 
    ibuprofen** 
 
 
 
Hydromorphone 
 
 
 
Morphine 
 
 
 
Oxymorphone 
 
 
 
Oxycodone 
 
 
 
Oxycodone/ 
   acetaminophen** 
 
 
 
Tramadol 
 
 
 
Tramadol / 
   acetaminophen** 
 
 
 
 
Fentanyl* (mcg) 
 
 
 
Other (specify) 
 
 
 
 


 
52 
 
14. 
 ADVERSE AND SERIOUS ADVERSE EVENTS (TABLES) 
 
14.1.     Adverse Events 
 
 
 
Treatment A 
                 
N= 
 
Treatment B 
 
N= 
 
Total 
 
N= 
P-value 
Nausea 
 
 
 
 
Vomiting 
 
 
 
 
Pruritis 
 
 
 
 
SPO2 < 95% requiring supplemental 
oxygen via nasal cannula due to opioid
therapy 
 
 
 
 
Moderate to Severe Sedation 
(Sedation Score of   > 3) 
 
 
 
 
Drowsiness 
 
 
 
 
Respiratory Depression not 
requiring intubation 
 
 
 
 
Low Blood Pressure  
(SBP< 90mmHg  
      and/or  
 DBP < 50 mmHg) 
 
 
 
 
 
 
 


 
53 
 
 
14.2. 
Serious Adverse Events 
 
 
 
Treatment A 
                 
N= 
 
Treatment B 
 
N= 
 
Total 
 
N= 
P-value 
 
Respiratory depression requiring 
naloxone administration given 
within the 2 hours of last 
administration of pain protocol drug 
 
             Mild  
             Moderate  
             Severe 
             Total 
 
 
 
 
 
Any event resulting in death  
  
             Mild  
             Moderate  
             Severe 
             Total 
 
 
 
 
 
Any event that is considered a life-
threatening complication 
 
             Mild  
             Moderate  
             Severe 
             Total 
 
 
 
 
 
Any event requiring admission to the 
Intensive Care Unit (ICU) 
 
             Mild  
             Moderate  
             Severe 
             Total 
 
 
 
 
 
Any event requiring intubation 
 
             Mild  
             Moderate  
             Severe 
             Total 
 
 
 
 
 
 
 
 


 
54 
 
15. 
HOSPITALIZATION (TABLE) 
 
 
15.1.    Hospitalization 
 
 
 
Treatment A 
                 
N= 
 
Treatment B 
 
N= 
 
Total 
 
N= 
P-value 
Hospitalization 
 
 
 
 
         Acute Chest Syndrome 
 
 
 
 
         Unresolved Pain 
 
 
 
 
         Other 
 
 
 
 
Admitted for ACS 
 
 
 
 
 
 
 


 
55 
 
16. 
ASSESSMENTS AT ED VISIT (TABLE) 
 
 
16.1.   Assessments 
 
 
 
Treatment A 
                 
N= 
 
Treatment B 
 
N= 
 
Total 
 
N= 
Pain Score 
        30 min 
        60 min 
        90 min 
      120 min 
      150 min 
      180 min 
      210 min 
      240 min 
      270 min 
      300 min 
      330 min 
      360 min 
        
 
 
 
Blood Pressure (SBP) 
        30 min 
        60 min 
        90 min 
      120 min 
      150 min 
      180 min 
      210 min 
      240 min 
      270 min 
      300 min 
      330 min 
      360 min 
 
 
 
 
Blood Pressure (DBP) 
        30 min 
        60 min 
        90 min 
      120 min 
      150 min 
      180 min 
      210 min 
      240 min 
      270 min 
 
 
 


 
56 
 
      300 min 
      330 min 
      360 min 
 
Heart Rate (RR) 
        30 min 
        60 min 
        90 min 
      120 min 
      150 min 
      180 min 
      210 min 
      240 min 
      270 min 
      300 min 
      330 min 
      360 min 
 
 
 
 
SpO2 
        30 min 
        60 min 
        90 min 
      120 min 
      150 min 
      180 min 
      210 min 
      240 min 
      270 min 
      300 min 
      330 min 
      360 min 
 
 
 
 
Sedation Score (0-4) 
        30 min 
        60 min 
        90 min 
      120 min 
      150 min 
      180 min 
      210 min 
      240 min 
      270 min 
      300 min 
      330 min 
      360 min 
 
 
 
 


 
57 
 
Respiration Rate (RR) 
        30 min 
        60 min 
        90 min 
      120 min 
      150 min 
      180 min 
      210 min 
      240 min 
      270 min 
      300 min 
      330 min 
      360 min 
 
 
 
 
 
 


 
58 
 
17. 
STUDY ENDPOINTS (TABLE) 
 
17.1.   Endpoints  
 
 
 
Treatment A 
                 
N= 
 
Treatment B 
 
N= 
 
Estimate 
(95% CIs), 
SD 
 
P-value 
Change in Pain Score  
(Primary Endpoint) 
 
 
 
 
Length of Index ED Stay 
 
 
 
 
Hospitalization for Pain Control 
 
 
 
 
Return ED Visits 
 
 
 
 
Hospitalizations (if not admitted to 
hospital on Index ED visit) 
 
 
 
 
Re-hospitalizations (if admitted to 
hospital on Index ED visit, but 
discharged) 
 
 
 
 
Day Hospital Visits 
 
 
 
 
ED Revisits or Hospital Re-admissions
or Day Hospital Visits Within 7 Days 
After the Index ED Visit (Binary 
Outcome with a Cutoff at Zero) 
 
 
 
 
Number of ED Revisits or Hospital 
Re-admissions or Day Hospital Visits 
After the Index ED visit 
 
 
 
 
 
17.2.   Endpoints (Sensitivity Analyses) 
 
 
 
Treatment A 
                 
N= 
 
Treatment B 
 
N= 
 
Estimate 
(95% CIs), 
SD 
 
P-value 
Change in Pain Score  
(Primary Endpoint) 
 
 
 
 
Length of Index ED Stay 
 
 
 
 
Hospitalization for Pain Control 
 
 
 
 
Return ED Visits 
 
 
 
 
Hospitalizations (if not admitted to 
hospital on Index ED visit) 
 
 
 
 
Re-hospitalizations (if admitted to 
hospital on Index ED visit, but 
discharged) 
 
 
 
 
Day Hospital Visits 
 
 
 
 
ED Revisits or Hospital Re-
admissions or Day Hospital Visits 
 
 
 
 


 
59 
 
Within 7 Days After the Index ED 
Visit (Binary Outcome with a Cutoff 
at Zero) 
Number of ED Revisits or Hospital 
Re-admissions or Day Hospital Visits 
within 7 days after the Index ED visit 
 
 
 
 
 
17.3.   Subgroup Analysis of the Primary Endpoint  
 
 
 
Treatment A 
                 
N= 
 
Treatment B 
 
N= 
 
Estimate 
(95% CIs), 
SD 
 
P-value 
Gender 
   Male 
   Female 
 
 
 
 
Age 
   < 30 
   >30 
 
 
 
 
Genotypes 
   SS + SB- 
    
   SC + SB+ 
    
 
 
 
 
Route 
   IV 
   SC 
 
 
 
 
NSAID 
   Yes 
   No 
 
 
 
 
Drug Administered  
   Yes 
   No 
 
 
 
 
Number of Repeated Doses 
     
 
 
 
 
Total Administered Milligrams of 
Drug  
    
 
 
 
 
 

Prot_001.pdf: 
1 
 
 
 
 
 
 
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 


2 
 
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  
 
 
 
 
 
 
 


3 
 
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 


5 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


6 
 
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 


7 
 
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 
 
 


8 
 
 
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. 


9 
 
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 
 


10 
 
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: 


11 
 
• 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. 
 


12 
 
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. 
 


14 
 
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 
 
 


18 
 
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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