Conditions: Musculoskeletal Pain
Keywords: Vitamin D Motor Vehicles Pain Racial Disparity
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 71
Healthy volunteers: yes

Brief summary:
The main objective of this study is to determine whether the administration of a single dose of Vitamin D in the Emergency Department following a motor vehicle collision can improve musculoskeletal pain severity as well as reduce musculoskeletal pain outcome disparity between Blacks and White following a motor vehicle collision. This randomized controlled trial is a pilot study to determine feasibility and potential efficacy (response to study drug, ability to reduce racial disparity in pain outcomes). This data can be used to adequately power a larger randomized controlled trial to fully assess efficacy.

Detailed description:
Motor vehicle collisions (MVCs) are one of the most common traumatic stress exposures in the US, and the most common for which individuals seek emergency department (ED) care. More than 1 million Black Americans (Blacks) come to the ED after MVC each year, and \>90% of such ED MVC patients are discharged home with a diagnosis of acute musculoskeletal pain (MSP)/strain only. More than 80% of these individuals report acute moderate or severe (mod/sev) MSP in the ED, and \>50% of those with acute mod/sev MSP transition to chronic MSP. MVCs, as well as pain after MVC, disproportionately affect Blacks vs. Whites. For example, in previous cohort studies 67% of Blacks had mod/sev MSP six months after MVC, vs. only 40% of Whites. Interventions are urgently needed that prevent chronic MSP and reduce these MSP outcome disparities.

One safe, inexpensive, widely available, and well-tolerated intervention, with exciting potential to achieve these goals, is Vitamin D (Vitamin D). The dose of Ergocalciferol that the investigators propose, 300,000 IU, has been shown to effectively raise Vitamin D concentration by \~9 ng/ml, and to raise serum 25 hydroxyvitamin D concentration above 30 ng/ml (Vitamin D sufficient levels) for over 3 months5. The ability of this single-dose protocol to raise Vitamin D will be a primary feasibility endpoint of this pilot study.

Importantly, this dose is extremely well-tolerated: in previous trials, reports of side effects/adverse events is rare,6 many studies administering single, high-dose regimens report no side effects7-9, and the most common side effects have been mild GI complaints (e.g. nausea).6 Vitamin D administration has also been demonstrated to be safe, even among individuals who are already Vitamin D sufficient. 10-12

Chronic pain is associated with reduced mental and physical health and interferes with essential activities of daily life. Currently there are limited treatment options to address chronic pain once it has become established and the overarching aim of this clinical trial is to prevent chronic pain development, therefore there is a critical unmet need of safe, non-addictive, non-invasive preventative treatment options that can be administered to MVC survivors in the aftermath of an injury. This study has the potential to benefit participants and future MVC survivors and improve pain and general health outcomes. The risks of taking Vitamin D are small. Side effects from Vitamin D are rare, however, it is possible that over supplementation of Vitamin D may be associated with headache, loss of appetite, dry mouth, metallic taste, and nausea/vomiting.

Primary Objective:

1. Assess the feasibility of the Randomized Controlled Trial (RCT) protocol by (a) calculating recruitment rate and participant retention, and (b) measuring the ability of Vitamin D administration to generate sustained increases in whole-blood Vitamin D concentrations (assessed 3 months after MVC).
2. To demonstrate the preliminary efficacy of Vitamin D administration per protocol on decreasing overall MSP severity during the 3 months following MVC, and reducing MSP outcome disparity between Blacks and Whites following MVC.

Secondary Objectives:

The investigators will assess the effect of race and sex on treatment outcomes in secondary analyses. This will be accomplished using two analytic strategies. First, a sex X treatment interaction term (secondary analyses) will be entered into the statistical models to assess pain reduction in response to treatment. Second, a stratified analysis will be performed which will examine the influence of both sex and race on treatment effect on primary and secondary outcomes. Further, Secondary stratified analyses evaluate the influence of initial vitamin D level on treatment response. In addition, exploratory analyses on the relationship of vitamin D outcome and trajectory of pain as well as restricting analyses to participants with vitamin D deficiency at baseline will be performed. Secondary analyses will examine treatment effects adjusting for any baseline differences in psychosocial factors between treatment arms.

Long-Term Aims Beyond the Present Proposal:

To use data collected to design and adequately power a larger-scale RCT assessing the efficacy of Vitamin D treatment in decreasing chronic pain in high-risk patients presenting for treatment in the aftermath of MVC and to reduce racial disparity in pain outcomes following MVC.

Described the sequence of events in recruiting 90 patients in a multi-center randomized controlled trial. To assess a key primary outcome, 50% white and 50% black MVC will be enrolled into the study. Each participant will be screened in based on a point of care Vitamin D test. This will be performed at the time of screening. Individuals with a Vitamin D level \<100 ng/ml will be enrolled. Patients will be randomized 1:1 to receive a single dose of 300,000 IU of ergocalciferol versus placebo and followed for 3 months. At 3 months, patients will send a blood sample easily collected at home on a blood spot card to assess Vitamin D level 3 months following injury which is a key feasibility primary outcome.

Patients presenting to the ED within 24 hours of MVC (n=90, 45 non-Hispanic Black, and 45 non-Hispanic White) will receive a single dose of study drug prior to ED discharge (1:1 allocation 300,000 IU ergocalciferol or placebo). Prior to study drug administration, a baseline assessment will be performed (see below), and a fingerstick blood sample will be obtained to evaluate 25-hydroxyvitamin D level. Telephone follow-ups assessing primary and secondary outcomes and potential adverse events will be performed 3 weeks, 6 weeks, and 3 months after ED enrollment by study Research Assistants using web-based REDCap™ software. At 3 months, participants will also perform fingerstick blood collection at home and mail to the study team to enable assessment of 3 month 25-hydroxyvitamin D concentration by treatment group.

Arms:
arm 1: 300,000 international units (IUs) of Ergocalciferol in 6 50,000 IU capsules. These will be given in a single dose prior to discharge from the Emergency Department. arm 2: Inert substance will be administered in 6 capsules indistinguishable from the 50,000 IU Ergocalciferol capsules administered in the active treatment arm.

Interventions: intervention 1: Vitamin D 2 intervention 2: Vitamin D2 Placebo
Intervention descriptions: intervention 1: 300,000 international units (IUs) of Ergocalciferol in 6 50,000 IU capsules. intervention 2: Inert substance will be administered in 6 capsules indistinguishable from the 50,000 IU

Protocol document:
ICF_002.pdf: 
 
 
Randomized Controlled Trial of Vitamin D to reduce racial 
disparity in chronic pain following Motor Vehicle Collision: The 
VENTURE Trial (Vitamin D to ENhance TraUma Recovery) 
 
 
NCT number 
NCT05458024 
Document Date 
08/29/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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INFORMED CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
AND HIPAA AUTHORIZATION TO DISCLOSE HEALTH INFORMATION  
 
CONSENT FORM 
FORM VERSION DATE:   8.29.23 
 
TITLE: 
Randomized Controlled Trial of Vitamin D to reduce racial 
disparity in chronic pain following Motor Vehicle Collision: The 
VENTURE Trial (Vitamin D to ENhance TraUma REcovery)  
UNC STUDY NUMBER: 
# 21-2589 
 
SPONSOR/FUNDING  
SOURCE: 
National Institutes of Health (NIH)/University of North Carolina  
 
INVESTIGATOR: 
Christopher W. Jones, MD 
 
Cooper University Hospital 
 
One Cooper Plaza 
 
Camden, NJ 08103 
 
INVESTIGATOR EMAIL: jones-christopher@cooperhealth.edu 
 
STUDY-RELATED 
PHONE NUMBER(S): 
(856) 342-2637 
 
 
Participant Name: ______________________________ 
Date of Birth: _____/_____/____ 
 
Concise Summary 
This is a research study to find out if vitamin D can help people recover from musculoskeletal 
pain (MSP) in the months following a car accident. In this study, we will ask that you complete 
an initial survey during your stay in the emergency department that will assess your initial pain 
following your car accident, as well as learn more about parts of your previous medical history. 
If you consent to be part of this study, we will ask for small blood samples from you today and in 
3 months to determine the vitamin D levels in your body. After today, we will ask you to 
complete surveys 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 9 weeks, and 3 months from 
today. These surveys can be completed on your smartphone, computer, or over the phone. There 
are risks to taking vitamin D that are described in this document. Side effects of vitamin D are 
rare but include headache, decreased appetite, dry mouth, metallic taste, and nausea/vomiting. If 
you agree to take part in this research study, there may not be a direct medical benefit to you.  


 
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We hope the information learned from this research study benefit participants and future MVC 
survivors and improve pain and general health outcomes. If you are interested in learning more 
about this study, please continue reading below. 
What are some general things you should know about research studies? 
You are being asked to take part in a research study.  To join the study is voluntary. 
You may choose not to participate, or you may withdraw your consent to be in the study, for any 
reason, without penalty. 
 
Research studies are designed to obtain new knowledge. This new information may help people 
in the future.   You may not receive any direct benefit from being in the research study. There 
also may be risks to being in research studies. Deciding not to be in the study or leaving the 
study before it is done will not affect your relationship with the researcher, your health care 
provider, or the University of North Carolina-Chapel Hill. If you are a patient with an illness, 
you do not have to be in the research study in order to receive health care. 
 
Details about this study are discussed below.  It is important that you understand this information 
so that you can make an informed choice about being in this research study.  
 
You will be given a copy of this consent form.  You should ask the researchers named above, or 
staff members who may assist them, any questions you have about this study at any time. 
 
What is the purpose of this study? 
The purpose of this research study is to learn about how people recover from musculoskeletal 
pain (MSP) following a car accident. You are being asked to be in the study because you 
received services through the emergency department and meet all eligibility criteria, which are 
listed below. The information gathered in this study will be used to help improve the care of 
individuals recovering from car accidents and other musculoskeletal injuries in the future. The 
use of Vitamin D is approved by the FDA. However, it is being used for a new indication in this 
study and therefore its use in this study is considered investigational or not approved by the 
FDA.  As part of this research, we are conducting surveys with participants seen at the 
emergency room after a car accident. During these surveys, we would like to find out about your 
overall health and well-being. You are being asked to be in the study because you received 
services through the emergency department, own a smartphone, have an email address, are 
willing to provide a blood sample, are willing to receive text messages, and are between the ages 
of 18-65. You will participate in the study today and for the next 3 months. 
 
Are there any reasons you should not be in this study? 
You should not be in this study if you are not willing to take vitamin D. You should not be in this 
study if you are pregnant or breastfeeding, are a prisoner, have known chronic kidney disease 
stage 4 or higher, have known hypercalcemia, take vitamin D supplements in excess of 800 IU 
daily, or do not speak and read English fluently. You should not participate in this study if you 
require(d) admission to the hospital, have a fracture, have a laceration with significant 


 
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hemorrhage, have an intracranial injury, have a self-inflicted injury, you have acute psychosis, 
thoughts of suicide, or harming others (homicide), experience ongoing domestic violence, or 
exceed the acceptable level of chronic daily opioid use (≥13mg oxycodone or equivalent). You 
should not be in this study if you are not non-Hispanic White and non-Hispanic Black.  
 
How many people will take part in this study? 
Approximately 90 people will be enrolled in this trial across four sites. Approximately 25 people 
will be enrolled at Cooper University Hospital. 
 
How long will your part in this study last? 
Your participation in the study will last for 3 months. If you choose to participate in the study, 
we will interview you for approximately 1 hour during your emergency department visit today. 
Over the next 3 months, you will be asked to complete 6 follow-up surveys which will take place 
in 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, and 3 months from today. The surveys 
occurring at weeks 2, 4, and 5 will be brief and will take you approximately 10 minutes to 
complete. These brief surveys will be sent to you via text messages and can be completed on 
REDCap, a smartphone-accessible, secure survey website. The surveys occurring 3 weeks, 4 
weeks, and 3 months from today will take you approximately 30 minutes each to complete. We 
will ask you to update your contact information 9 weeks from today which will take about 5 
minutes to complete. All surveys can be sent to your email or cell phone number to be completed 
online (on REDCap) or can be completed over the phone. Finally, 3 months from today, you will 
be asked to put a small (3 drops) blood sample onto a blood spot card via a fingerstick. You will 
send this prepaid and pre-addressed card to the study team by dropping it in the mail.  
 
What will happen if you take part in the study? 
Your participation in this study will not affect your treatment plan between you and your 
physician. After reading and signing this consent form, your participation will begin with the 
initial interview during which an initial baseline assessment will be administered. You may 
refuse to answer any of these questions. After this initial assessment, we will ask for you to 
provide a small blood sample which we will use to check the vitamin D levels in your blood. 
This blood sample will be obtained using a fingerstick with a small, sterile lancet. If you are 
having blood drawn for lab work during your visit in the emergency department, you may choose 
to consent to having your blood sample taken from this blood draw. Following the collection of 
the blood sample, you will be asked to fill out a baseline questionnaire. This questionnaire will 
collect information regarding your demographic information (e.g. age, sex, race), the details of 
your pain following your car accident, and information regarding medications you may be 
taking. After you have completed the questionnaire, you will be randomized into one of two 
groups, either the group receiving vitamin D or the placebo. This selection is based on chance, 
and you or your treating physician will not know which group you are assigned to. A urine 
pregnancy test will be done on all females who might be able to get pregnant at the start of the 
study. The cost of the pregnancy test of applicable participants will be covered by the study. 


 
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If you agree to participate in the study, we will provide you with instructions on follow-up 
surveys which we will ask you to complete 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 9 
weeks, and 3 months from today. Additionally, you will be provided with the supplies and 
instructions to complete a fingerstick blood draw, similar to the one that will be done in the 
emergency department today, at home 3 months from today. You will then send this prepaid and 
pre-addressed card to the study team by dropping it in the mail. If you happen to misplace these 
materials before the end of the 3-month period, we will send you a replacement kit to your home. 
What are the possible benefits from being in this study? 
If you agree to take part in this research study, there may not be a direct medical benefit to you.  
We hope the information learned from this research study will benefit other patients with who 
have been involved in a motor vehicle accident in the future.  Potential benefits to you may 
include more frequent than usual medical exams/assessments. 
 Studies that use specimens from this repository/biobank may provide additional information that 
will be helpful in understanding the recovery process after a motor vehicle collision and may 
contribute to identifying better treatments for people who experience pain after motor vehicle 
collision. 
 
What are the possible risks or discomforts involved from being in this study? 
Interviews: We will be collecting data about your injury and your overall health; every attempt 
will be made to protect this information. There is a very small risk of a breach of confidentiality 
during this study. This risk will be minimized by keeping your information on a secure database 
(REDCap), training of research personnel involved in the study, and we will de-identify your 
personal information on blood samples.  
Blood draws: Very rarely, drawing blood from a finger stick may cause discomfort, bruising, 
prolonged bleeding, and infection at the site of puncture.  To minimize risk, we will swab the site 
of puncture with alcohol to disinfect the area, use disposable lancet and capillary tubes to collect 
blood, and apply pressure to the puncture site following the blood draw to minimize bruising.  
We will cover the puncture with an appropriate dressing. 
Emotional Discomfort Risks: You will be asked to answer questions regarding the nature of 
your accident and the pain you have experienced as a result, which may cause some emotional 
discomfort or distress. You may choose not to answer any questions you find too distressing.  
 
Consumption of Vitamin D: The use of Vitamin D is approved by the FDA. However, it is 
being used for a new indication in this study. Vitamin D is safe, well-tolerated, and widely 
available. Consumption of Vitamin D has been shown to be safe in previous studies. The risk of 
taking this supplement is small. Side effects of Vitamin D are rare, but include headache, 
decreased appetite, dry mouth, metallic taste, and nausea/vomiting.  
If you experience any discomforts, inform the study doctor immediately.  


 
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There may be uncommon or previously unknown risks. You should report any problems to the 
researcher. 
 
If you choose not to be in the study, what other treatment options do you have? 
You do not have to participate in this study to receive treatment of your symptoms from the 
motor vehicle accident. While you are in the study your study doctor can recommend the best 
treatment for your symptoms.  
 
What if we learn about new findings or information during the study?  
You will be given any new information gained during the course of the study that might affect 
your willingness to continue your participation. 
  
How will information about you be protected? 
Records of your participation in this study will be secured in the data coordinating center.  No 
subjects will be identified in any report or publication about this study.  Although every effort 
will be made to keep research records private, there may be times when federal or state law 
requires the disclosure of such records, including personal information.  This is very unlikely, 
but if disclosure is ever required, UNC-Chapel Hill will take steps allowable by law to protect 
the privacy of personal information.  In some cases, your information in this research study could 
be reviewed by representatives of the University, research sponsors, or government agencies for 
purposes such as quality control or safety. We may use de-identified data and/or specimens from 
this study in future research without additional consent. 
A federal law called the Genetic Information Nondiscrimination Act (GINA) states that it is 
illegal for covered entities to disclose genetic information about their applicants, employees or 
members without consent. There are limited exceptions; however, in general, such entities must 
keep the individual’s genetic information confidential. A New Jersey law called The Genetic 
Privacy Act states that a person’s genetic information is private property and cannot be collected, 
retained, or disclosed without written consent. Under both of these laws, it is illegal for health 
insurance companies and employers to require anyone to give these companies genetic 
information about another person without the other person’s written consent. The federal and 
New Jersey laws also state that if an insurance company or employer should somehow obtain 
genetic information about a client or employee, it is illegal for them to use the genetic 
information to discriminate against that client or employee. Insurance companies may not use 
any genetic information they might obtain to make decisions about coverage, rates, or 
preexisting conditions. Employers may not use any genetic information that they might obtain 
for decisions about hiring, firing, or promotion.  
 
The federal law does not cover life, disability, or long-term care insurance. For example, life 
insurance companies may in the future decide to ask if you have ever had genetic tests for cancer 
susceptibility when you apply for a new policy. However, the New Jersey law prohibits 


 
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companies that sell life, disability, or long-term care insurance from using genetic information 
for unfair discrimination.  
 
By signing this informed consent document, you agree that some of the information generated by 
participating in this study and/or a copy of the consent form may be included in your medical 
record and that this information may be viewed by other physicians or caregivers who provide 
healthcare services to you. This will allow the doctors caring for you to know what study 
medications or tests you may be receiving as a part of the study and know how to take care of 
you if you have other health problems or needs during the study. Additionally, the information 
may be shared with your medical insurance plan if the research services provided are billed to 
your insurance. 
 
To help us protect your privacy, we have a Certificate of Confidentiality from the FDA.  With 
this Certificate, we cannot be forced to disclose information that may identify you, even by a 
court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings, except when release of that information is required for auditing or evaluation of 
federally funded projects or to meet the requirements of the federal Food and Drug 
Administration (FDA).  A Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research, as you are free to do that at any time.  If an insurer, employer, or other person obtains 
your written consent to receive research information, then we will not use the Certificate to 
withhold that information.  In the event that information regarding intent to harm yourself or 
others, including child abuse, becomes known to us, we are required by law to divulge this 
information even without your consent. 
 
What is a Certificate of Confidentiality?  
This research is covered by a Certificate of Confidentiality. With this Certificate, the researchers 
may not disclose or use information, documents or biospecimens that may identify you in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings in the 
United States, for example, if there is a court subpoena, unless you have consented for this use. 
 
The Certificate cannot be used to refuse a request for information from personnel of a federal or 
state agency that is sponsoring the study for auditing or evaluation purposes or for information 
that must be disclosed in order to meet the requirements of the federal Food and Drug 
Administration (FDA). 
 
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, 
state, or local law, such as mandatory reporting requirements for child abuse or neglect, disabled 
adult abuse or neglect, communicable diseases, injuries caused by suspected criminal violence, 
cancer diagnosis or benign brain or central nervous system tumors or other mandatory reporting 
requirement under applicable law. The Certificate of Confidentiality will not be used if 
disclosure is for other scientific research, as allowed by federal regulations protecting research 
subjects or for any purpose you have consented to in this informed consent document. 


 
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You should understand that a Certificate of Confidentiality does not prevent you from 
voluntarily releasing information about yourself or your involvement in this research. If an 
insurer, employer, or other person obtains your written consent to receive research information, 
then the researchers may not use the Certificate to withhold that information. 
 
What will happen if you are injured by this research? 
All research involves a chance that something bad might happen to you.  This may include the 
risk of personal injury. In spite of all safety measures, you might develop a reaction or injury 
from being in this study. If such problems occur, the researchers will help you get medical care, 
but any costs for the medical care will be billed to you and/or your insurance company. The 
University of North Carolina at Chapel Hill has not set aside funds to pay you for any such 
reactions or injuries, or for the related medical care. You do not give up any of your legal rights 
by signing this form. 
If you think you have been injured from taking part in this study, call the study team at the phone 
number provided on this consent form.  They will let you know what you should do.  
By signing this form, you do not give up your right to seek payment or other rights if you are 
harmed as a result of being in this study. 
If you believe that you have been injured or become ill because you took part in this study, you 
should call the Chief Medical Officer or their representative at (856) 342-3071. 
What if you want to stop before your part in the study is complete? 
You can withdraw from this study at any time, without penalty.  The investigators also have the 
right to stop your participation at any time. This could be because you have had an unexpected 
reaction, or have failed to follow instructions, or because the entire study has been stopped. 
 
If you withdraw or are withdrawn from this study all data collected up until the point of 
withdrawal will be retained, however, no additional information will be collected unless you 
provide additional written permission for further data collection at the time of your withdrawal. 
Will you receive anything for being in this study? 
You will be compensated up to $420 for completing study activities. The below table provides an 
overview of the study activity and what you can earn for completing it. 
Study Activity 
When Available 
Number Available 
Throughout 
Participation 
Payment Per 
Completion 
Total Possible 
Payment for 
Completing All 
Blood Draw 
Day of Enrollment 
1 
$10 
$10 
Brief “Flash” Surveys 
2 weeks, 4 weeks, 5 weeks 
3 
$20 
$60 
Surveys 
3 weeks, 6 weeks, 3 months 
3 
$60 
$180 


 
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Updating Contact 
Information 
9 weeks 
1 
$10 
$10 
3 Drops of Blood on 
Card 
3 months 
1 
$60 
$60 
Total 
$320 + Bonus 
 
In addition to receiving payments for completing study activities, you can also receive bonus 
payments for completing the majority of the study activities.  
Bonus Payments 
Number of Missed 
Study Activities 
Bonus Amount 
0 
$100 
1 
$80 
2 
$60 
3 
$30 
 
These payments will be sent to your email via electronic gift cards following your enrollment in 
the emergency department. Electronic gift cards will be sent within the two weeks after 
completing a study activity. Any payment provided for participation in this study may be subject 
to applicable tax withholding obligations. 
 
 
Your name, address, and U.S. tax payer identification number (SSN or ITIN) are required to 
process payments and/or to report taxable income to the IRS.  You must complete a W-9 (for 
U.S. persons) or W-8BEN and the Foreign Vendor Withholding Assessment with supporting 
documents (for non-resident aliens) in order to receive payment for participation. 
 
U.S. person participants must complete Form W-9 in order to receive payment for 
participation.  If payment by UNC equals or exceeds $600 per calendar year for U.S. persons, 
UNC will report the amount to the Internal Revenue Service on Form 1099.  Nonresident alien 
participants must complete Form W-8BEN and the Foreign Vendor Withholding Assessment 
with supporting documents in order to receive payment for participation.  Payments to 
nonresident alien participants may be subject to tax withholding and are generally reported to the 
Internal Revenue Service on Form 1042-S.  This information will not be linked to any of the 
study data and will only be used for payment purposes. 
 
If you do not provide your SSN or ITIN, or complete the appropriate documentation noted 
above, we cannot issue you a payment for participation.  However, you may still choose to 
participate in this study. 
 
Will it cost you anything to be in this study? 
It will not cost you anything in addition to what you will be billed for your routine medical care 
to be in this study. All tests, visits, or procedures other than what is done for this study will be 


 
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related to medical care that is part of the usual care for your condition and would be suggested 
even if you decided not to be in the research study. Examples of standard medical care that may 
be performed include ECGs (electrocardiogram, which is a painless test to measure the electrical 
activity in your heart), a pregnancy test, X-Ray, CT scan, MRI, or other imaging, etc. 
Who is sponsoring this study? 
This research is funded by the National Institute of Health (NIMHD), the UNC Department of 
Anesthesiology, and the Institute for Trauma Recovery.  This means that the research team is 
being paid by the sponsors for doing the study.  The researchers do not, however, have a direct 
financial interest with the sponsor or in the final results of the study. 
 
What if you have questions about this study? 
You have the right to ask, and have answered, any questions you may have about this research. If 
you have questions about the study (including payments), complaints, concerns, or if a research-
related injury occurs, you should contact the researchers listed on the first page of this form. 
 
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. 
Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time. 
What if you have questions about your rights as a research participant? 
All research on human volunteers is reviewed by a committee that works to protect your rights 
and welfare.  If you have questions or concerns about your rights as a research subject, or if you 
would like to obtain information or offer input, you may contact the Institutional Review Board 
at 919-966-3113 or by email to IRB_subjects@unc.edu. 
You may contact the Cooper Human Research Protections Program (HRPP) if you have 
questions about this research or about your rights as a research participant at (856) 757-7832. 
The mailing address of the Cooper HRPP is E&R Building, 401 Haddon Ave., Room 288, 
Camden, NJ 08103. You may contact the HRPP (a) if you believe that you have not been told 
about all the risks, benefits, and alternative treatments, (b) if you believe that you are being 
forced to stay in this study when you do not want to, or (c) you have any complaints about the 
research. 
HIPAA AUTHORIZATION 
 
We call your health information that identifies you your “protected health information” or “PHI.”  
To protect your PHI, we will follow federal and state privacy laws, including the Health 
Insurance Portability and Accountability Act and regulations (HIPAA). If you sign this form, 
you are giving the investigators, their staff, and certain other people described in this form your 
permission to use your protected health information for this research study. 
What information about you will be collected or used? 


 
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To do this research, we will collect information about you and your health conditions. Some 
information about you will also be collected from your medical records. The information 
collected will be used to determine if you qualify to participate in this research, to follow your 
treatment and contact you, and to answer the research questions. 
 
The following PHI will be collected or used as part of this research study: 
• Identifiers such as your name, medical record number, and contact information  
• Personal medical history including present and past medications 
• Results of exams, procedures, and tests you have before and during the study 
• Your social security number may need to be collected in order to process your study 
payments 
• Social history including tobacco, drug and alcohol use 
• Research Study records 
 
Who will use or have access to your protected health information? 
By signing this form, you are allowing the following people or groups to have access to your 
PHI: 
• The research team, which includes the investigator listed on this form and other personnel 
involved in this study, in order to support the study and analyze the data. 
• Others employed or contracted by Cooper, if needed for your clinical care or study 
oversight. To improve coordination of your research and clinical care, some information 
about the study may be added to your electronic medical record.     
• Cooper’s Human Research Protections Program, including the IRB, may look at your 
study records to ensure the research is being conducted appropriately. 
 
All of these people and entities are obligated to protect your PHI. 
You are also allowing your PHI to be used by or shared with other people or groups 
specified below: 
• The Office for Human Research Protection (OHRP). OHRP is an office that oversees 
research funded by the federal government and oversees the IRB at Cooper University 
Hospital.  
• The National Institute of Health (NIH). The NIH may need to be sure the records are 
accurate and that the research is done according to NIH regulations.  


 
IRB TEMPLATE Version 2.1 - 1/17/2020 - Do not alter this text box 
 
21-2589Adult Consent Form Page 11 of 12 
• UNC, the study sponsor, and its agents or contractors, who may need to access your PHI 
in order to monitor the study, to ensure that the research records are accurate, and to 
analyze the research data.  
 
Although these entities listed above have their own confidentiality procedures to protect your 
PHI, they are not covered by the same federal privacy rule, HIPAA, that governs healthcare 
providers, and therefore they are not bound to its regulations. 
How will your information be kept confidential? 
To help maintain the confidentiality of your study records, we will replace your name and any 
identifying information with a code. Your identifying information will be stored securely and 
separately from the rest of the research records. All study documents will be stored in a locked 
file cabinet or in a password-protected secured electronic environment. Only authorized study 
personnel will have access to your identifiable information. 
We may publish the information from this study in scientific journals or present it at scientific 
meetings, but you will not be personally identified in these publications and presentations. It is 
possible that the data collected for this study may be useful for future research conducted at 
Cooper or by other investigators outside of Cooper. We will remove all of the information that 
identifies you, such as your name. This de-identified data may be used or shared with other 
investigators for future research studies without additional informed consent from you. 
Please note: Healthcare providers are required to share with the New Jersey Department of 
Health any confirmed diagnosis of over 70 communicable diseases, including but not limited to 
HIV/AIDS, Hepatitis, Measles and others (N.J. Admin. Code § 8:57-1.5). If in the course of this 
study, you are diagnosed with any of the diseases listed under New Jersey law, your name, 
address, and phone number will be shared with the Department of Health. In addition, under 
New Jersey Law (N.J. Admin. Code § 8:40-3.7) there is a requirement for certain individuals to 
report any reasonable belief of child or elder abuse to the New Jersey Department of Health 
(DOH), and in the case of child abuse, the Division of Child Protection and Permanency 
(DCPP). If in the course of this study, there exists a reasonable belief of child or elder abuse 
then relevant contact information will be shared with New Jersey DOH and DCPP as required 
by law. 
Do you have to give authorization for use of your PHI?  
No, but if you do not give this authorization then you cannot join the study. This will not affect 
the medical care that you receive outside of the study. 
How long will your information be collected, used or shared? 


 
IRB TEMPLATE Version 2.1 - 1/17/2020 - Do not alter this text box 
 
21-2589Adult Consent Form Page 12 of 12 
Your authorization for the collection, use, and sharing of your PHI for this specific study does 
not expire. 
Please note that Cooper may not re-use or re-disclose information collected in this study for a 
purpose other than this study unless: 
• You have given written authorization  
• The Institutional Review Board grants permission 
• As permitted by law 
 
What if you change your mind? 
You may revoke this authorization to use and share your PHI at any time by contacting the principal 
investigator, in writing, at the address listed on the first page of this form. 
If you decide not to authorize the investigator to use and disclose your PHI or you revoke this 
authorization, you will no longer be able to participate in this research study, and the use or sharing 
of future PHI will be stopped. However, the PHI that has already been collected may still be used.   
 
Consent/HIPAA Authorization Signature Section:  
Signature Page for Adult Subjects 
SUBJECT: 
Printed Name of Subject: _________________________________ 
Signature: ______________________ Date: ___________ Time: __________ 
 
INVESTIGATOR: I have discussed the study described above with the subject.  
Printed Name of Investigator Obtaining Consent: ________________________ 
Signature: ______________________ Date: ___________ Time: __________ 
 
WITNESS: 
Printed Name of Witness to Subject’s Signature: _________________________ 
Signature: ______________________ Date: ___________ Time: __________ 
 

Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
 
 
 
Randomized Controlled Trial of Vitamin D to reduce racial disparity in 
chronic pain following Motor Vehicle Collision: The VENTURE Trial 
(Vitamin D to ENhance TraUma REcovery) 
 
 
 
 
 
NCT number NCT05458024 
Document Date 11/12/2021 
 
 


VENTURE Trial  
 
 
 
 
 
 
 
 
 
Page ii 
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Protocol Title: 
Randomized Controlled Trial of Vitamin D to reduce racial disparity in chronic pain following 
Motor Vehicle Collision: The VENTURE Trial (Vitamin D to ENhance TraUma REcovery) 
 
 
Principal Investigators: 
Matthew C. Mauck, MD PhD 
Department of Anesthesiology 
Campus Box 7010 
Chapel Hill, NC 27599 
 
Samuel McLean, MD, MPH 
Professor of Emergency Medicine, Psychiatry, and 
Anesthesiology 
101 Manning Drive 
Chapel Hill, NC 27599 
 
Funding Sponsor: 
 
 
 
 
 
 
University of North Carolina 
N2198 UNC Hospitals 
Campus Box 7010 
Chapel Hill, NC 27599 
 
Study Product: 
Ergocalciferol  
Protocol Number: 
21-2589 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Initial version: [11.12.2021] 
Table of Contents 
 
Study Summary ..................................................................................................................... 1 
Introduction .......................................................................................................................... 2 
1.1 
Background ..........................................................................................................................2 
1.2 
Investigational Agents ..........................................................................................................3 
1.3 
Clinical Data to Date .............................................................................................................4 
1.4 
Dose Rationale and Risk/Benefits ..........................................................................................4 
Study Objectives .................................................................................................................... 4 
2.1 
Primary Objective: ................................................................................................................5 
2.2 
Secondary Objectives:...........................................................................................................5 
2.3 
Long-Term Aims Beyond the Present Proposal .......................................................................5 
Study Design ......................................................................................................................... 5 
3.1 
General Design .....................................................................................................................5 
3.2 
Study Overview ....................................................................................................................6 
3.3 
Posting on clinicaltrials.gov ...................................................................................................6 
3.4 
Primary Study Endpoints .......................................................................................................6 
3.5 
Primary Safety Endpoints ......................................................................................................7 
3.6 
Inclusion Criteria ..................................................................................................................7 
3.7 
Exclusion Criteria ..................................................................................................................7 
3.8 
Subject Recruitment and Screening .......................................................................................8 
3.9 
Early Withdrawal of Subjects ................................................................................................9 
3.9.1 
When and How to Withdraw Subjects ................................................................................................... 9 
3.9.2 
Data Collection and Follow-up for Withdrawn Subjects ........................................................................ 9 
Study Drug ............................................................................................................................ 9 
4.1 
Description ...........................................................................................................................9 
4.2 
Treatment Regimen ..............................................................................................................9 
4.3 
Method for Assigning Subjects to Treatment Groups .............................................................9 
4.4 
Preparation and Administration of Study Drug .................................................................... 10 
4.5 
Subject Compliance Monitoring .......................................................................................... 10 
4.6 
Prior and Concomitant Therapy........................................................................................... 10 
4.7 
Packaging ........................................................................................................................... 10 


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4.8 
Blinding of Study Drug (if applicable) ................................................................................... 10 
4.9 
Receiving, Storage, Dispensing and Return .......................................................................... 11 
4.9.1 
Receipt of Drug Supplies ...................................................................................................................... 11 
4.9.2 
Storage ................................................................................................................................................. 11 
4.9.3 
Dispensing of Study Drug ..................................................................................................................... 11 
4.9.4 
Return or Destruction of Study Drug ................................................................................................... 11 
Study Procedures ................................................................................................................. 11 
5.1 
Enrollment Procedures ....................................................................................................... 11 
5.2 
Emergency Department Medication Administration ............................................................ 13 
5.3 
Data Extraction ................................................................................................................... 13 
5.4 
Text messaged or e-mailed outpatient Weekly Pain and Compliance Assessments ............... 13 
5.5 
3 and 6-week assessment ................................................................................................... 14 
5.6 
3-month assessment ........................................................................................................... 14 
Statistical Plan .................................................................................................................... 14 
6.1 
Outcome definitions/Analysis plan/Power calculation ......................................................... 14 
6.2 
Subject Population(s) for Analysis ....................................................................................... 16 
Safety and Adverse Events ................................................................................................... 16 
7.1 
Definitions.......................................................................................................................... 16 
7.2 
Recording of Adverse Events ............................................................................................... 18 
7.3 
Reporting of Serious Adverse Events and Unanticipated Problems ....................................... 19 
7.3.1 
Investigator reporting .......................................................................................................................... 19 
7.4 
Unblinding Procedures ........................................................................................................ 21 
7.5 
Stopping Rules .................................................................................................................... 21 
7.6 
Medical Monitoring ............................................................................................................ 21 
7.7 
Confidentiality .................................................................................................................... 23 
7.8 
Source Documents .............................................................................................................. 24 
7.9 
Case Report Forms (as applicable) ....................................................................................... 24 
7.10 Records Retention ................................................................................................................. 24 
Study Monitoring, Auditing, and Inspecting ......................................................................... 24 
8.1 Study Monitoring Plan............................................................................................................. 24 
8.2 
Auditing and Inspecting ...................................................................................................... 25 
Ethical Considerations ......................................................................................................... 25 
Study Finances..................................................................................................................... 25 
10.1 
Funding Source ............................................................................................................... 25 
10.2 
Conflict of Interest .......................................................................................................... 26 


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10.3 
Subject Stipends or Payments .......................................................................................... 26 
Publication Plan .................................................................................................................. 26 
Data Management Plan ...................................................................................................... 26 
References........................................................................................................................... 27 
Appendices .......................................................................................................................... 30 
14.1 Appendix 1: Adverse Event Monitoring and Stopping Rules Table ........................................... 30 
 
 
 


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List of Abbreviations 
 
AE: Adverse Events 
cc: cubic centimeters 
CRF: case report form 
DASS: Depression, Anxiety, and Stress Scale 
DCC: data coordinating center 
DNA: deoxyribonucleic acid 
EC: ethics committee 
ELISA: enzyme linked immunosorbent assay 
FDA: Food and Drug Administration 
g: grams 
GFR: glomerular filtration rate 
IDS: investigational drug services 
IRB: institutional review board 
IU: international units 
MAR: medication administration record 
MCS: mental component score 
MSP: severe musculoskeletal pain 
MOS: medical outcomes survey 
MVC: motor vehicle collision  
NRS: numeric rating scale 
OT: occupational therapy 
PCS: physical component score 
PT: physical therapy 
PTSD: post-traumatic stress disorder 
RCT: Randomized Controlled Trial 
RNA: ribonucleic acid 
RPS: regional pain scale 
SAE: serious adverse events 
SF-12: short form 12 item questionnaire 
TBSA: total body surface area 
UNC: University of North Carolina 
UPLC/ESI/MS/MS: Ultraperformance Liquid Chromatography/Electrospray Ionization Mass 
Spectrometry 


[Insert short name of protocol here] 
 
page 1 
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CONFIDENTIAL 
Study Summary 
 
Title 
Randomized Controlled Trial of Vitamin D to reduce racial disparity 
in chronic pain following Motor Vehicle Collision 
Short Title 
VENTURE 
IRB Protocol Number 
21-2589 
Phase 
2 
Methodology 
Double Blind, Randomized Controlled Trial using a parallel design 
Study Duration 
2 years 
Study Center(s) 
University of North Carolina-Data Coordinating Center 
Rhode Island Hospital 
University of Massachusetts 
Washington University 
Cooper University Hospital 
Objectives 
Assess the feasibility of administering a single dose of Vitamin D in 
the emergency department to Blacks and Whites presenting 
within 24 hours of MVC with moderate or severe musculoskeletal 
pain (MSP), along with the ability of this dose to achieve sustained 
increases in Vitamin D levels. Evaluate the potential efficacy of this 
intervention to improve MSP outcomes in Blacks and to reduce 
MSP disparities in Black vs. White MVC survivors. 
Number of Subjects 
90 
Diagnosis and Main 
Inclusion Criteria 
Presentation to emergency department (ED) within 24 hours of 
motor vehicle collision with an initial moderate/severe MSP 
severity (0-10 NRS of ≥4) 
Study Product, Dose, 
Route, Regimen 
Ergocalciferol (Vitamin D2), 300,000 IU (2-150,000 IU capsules) 
orally administered once as a single dose prior to discharge from 
emergency department 
Duration of 
administration 
One-time dose 
Reference therapy 
Matched placebo to Vitamin D preparation 


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Statistical Methodology 
Assess the feasibility of the RCT protocol by (a) calculating 
recruitment rate and participant retention, and (b) measuring the 
ability of Vitamin D administration to generate sustained increases 
in whole-blood Vitamin D concentrations (assessed 3 months after 
MVC). Assess for preliminary efficacy that Vitamin D 
administration per protocol (a) decreases overall MSP severity in 
Black Americans during the 3 months following MVC, and (b) 
reduced MSP outcome disparities between Black vs. White 
Americans following MVC. 
Introduction 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures.  
 
The main objective of this study is to determine whether administration of a single dose of 
Vitamin D in the Emergency Department following a motor vehicle collision reduces racial 
disparities in chronic pain following a traumatic event. This phase II, multicenter, randomized 
controlled trial is a pilot study to determine feasibility and potential efficacy (effect size, sample 
variation, response to study drug, ability to reduce racial disparity in pain outcomes) that can be 
used to adequately power a larger randomized controlled trial to fully assess efficacy.  
1.1 Background 
Motor vehicle collisions (MVCs) are one of the most common traumatic stress exposures in the 
US, and the most common for which individuals seek emergency department (ED) care. More 
than 1 million Black Americans (Blacks) come to the ED after MVC each year, and >90% of such 
ED MVC patients are discharged home with a diagnosis of acute musculoskeletal pain 
(MSP)/strain only. More than 80% of these individuals report acute moderate or severe 
(mod/sev) MSP in the ED, and >50% of those with acute mod/sev MSP transition to chronic 
MSP. MVCs, as well as pain after MVC, disproportionately affect Blacks vs. Whites. For example, 
in our previous cohort studies 67% of Blacks had mod/sev MSP six months after MVC, vs. only 
40% of Whites. Interventions are urgently needed that prevent chronic MSP and reduce these 
MSP outcome disparities. 
 
One safe, inexpensive, widely available, and well-tolerated intervention, with exciting potential 
to achieve these goals, is Vitamin D (Vitamin D). Vitamin D insufficiency is much more common 
in Blacks than Whites. In the investigators’ previous observational study, 77% (103/133) of 
Black MVC survivors had Vitamin D insufficiency at the time of ED evaluation. Such low Vitamin 
D levels are associated with increased inflammation and worse pain outcomes. Vitamin D has 
anti-inflammatory, neuroprotective, and analgesic properties, and Vitamin D treatment 
improves pain outcomes in a range of conditions. Results of a recent Vitamin D intervention 
study in another trauma population (burn survivors) found that Vitamin D treatment after burn 


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injury disproportionately improved pain outcomes in Black vs. White burn survivors (67% vs. 
33% pain improvement at 6 weeks). Results from a recent analysis suggest that Vitamin D 
administration in the ED after MVC could prevent at least 70,000 Blacks from developing 
chronic post-MVC MSP annually. 
1.2 Investigational Agents 
Some previous treatment trials of Vitamin D have elected to use Cholecalciferol (D3), rather 
than Ergocalciferol (D2), because of more favorable kinetics.1 However, both have efficacy in 
raising serum concentration of 25-hydroxyvitamin D,2 and only Ergocalciferol (D2) is available in 
an FDA-approved prescription formulation that is well-tolerated.3,4 In addition, a major benefit 
of Ergocalciferol (D2) is that a single dose can result in Vitamin D sufficient levels for many 
weeks/months (Table 1). The dose of Ergocalciferol that we propose, 300,000 IU, has been 
shown to effectively raise Vitamin D concentration by ~9 ng/ml, and to raise serum 25 
hydroxyvitamin D concentration above 30 ng/ml (Vitamin D sufficient levels) for over 3 months5. 
The ability of our single-dose protocol to raise Vitamin D will be a primary feasibility endpoint of 
this pilot study.  
 
Importantly, this dose is extremely well-tolerated: in previous trials, reports of side 
effects/adverse events is rare,6  many studies administering single, high-dose regimens report 
no side effects7-9, and the most common side effects have been mild GI complaints (e.g. 
nausea).6 Vitamin D administration has also been demonstrated to be safe, even among 
individuals who are already Vitamin D sufficient. 10-12 Based on the Code of Federal Regulation 
(CFR), Ergocalciferol will be exempt from an investigational new drug (IND) application.5,13-16  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1. Studies demonstrating effectiveness of single-dose Vitamin D 
(Ergocalciferol, D2) to raise 25-hydroxyvitamin D levels 
First author/year 
Dose Used 
Sample 
Size 
Disease 
state 
Magnitude increases 
of 25-OH Vitamin D 
@ timepoint 
Martineau et al, 
200713 
100,000 IU 
(PO) 
N=192 
Tuberculosis 
patients 
↑ 13 ng/ml @ 6 
weeks 
Witham, et al, 
201214 
100,000 IU 
(PO) 
N=58 
Stroke 
↑ 6 ng/ml @ 8 
weeks 
Lanthan et al, 
20035 
300,000 IU 
(PO) 
N=243 
Frail elderly 
↑ 9 ng/ml @ 12 
weeks 
Alam, et al,  201715 
600,000 IU 
PO 
N=143 
Diabetic 
neuropathy 
↑ 10 ng/ml @ 20 
weeks 
Cipriani et al, 2013 
16 
600,00 IU 
PO 
N=6 
Healthy 
Volunteers 
↑ 6 ng/ml @ 4 
weeks 


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1.3 Clinical Data to Date 
Previous studies demonstrate that Vitamin D is a safe, and effective treatment option that has 
been used to treat a range of painful musculoskeletal disorders. Vitamin D has been shown to 
reduce chronic pain across a range of painful conditions. Clinical trial results demonstrate that 
Vitamin D supplementation improves symptoms experienced by patients suffering from 
fibromyalgia17-21, a difficult to treat widespread pain condition. Vitamin D supplementation in a 
recent clinical trials also improved disability related to low back pain22, osteoarthritis23 and 
chronic pain related to migraine headache24. Not all studies are positive, for example a recent 
study demonstrated that Vitamin D supplementation did not change analgesic consumption, or 
improve pain outcomes among the general population25; however this study included the 
general population not those at high risk of chronic pain development as are the individuals we 
plan to recruit into this study. Taken together, the results of clinical trials of Vitamin D to 
address painful conditions are promising, and given the lack of available treatment options to 
prevent chronic pain.  
1.4 Dose Rationale and Risk/Benefits 
The dose of Ergocalciferol that we propose, 300,000 IU, has been shown to effectively raise 
Vitamin D concentration by ~9 ng/ml, and to raise serum 25 hydroxyvitamin D concentration 
above 30 ng/ml (Vitamin D sufficient levels) for over 3 months5. The ability of our single-dose 
protocol to raise Vitamin D will be a primary feasibility endpoint of this pilot study. Importantly, 
this dose is extremely well-tolerated: in previous trials, reports of side effects/adverse events is 
rare,6  many studies administering single, high-dose regimens report no side effects7-9, and the 
most common side effects have been mild GI complaints (e.g. nausea).6 Vitamin D 
administration has also been demonstrated to be safe, even among individuals who are already 
Vitamin D sufficient. 10-12 Based on the Code of Federal Regulation (CFR), Ergocalciferol will be 
exempt from an investigational new drug (IND) application.5,13-16  
 
Chronic pain is associated with reduced mental and physical health and interferes with essential 
activities of daily life. Currently there are limited treatment options to address chronic pain 
once it has become established and the overarching aim of this clinical trial is to prevent 
chronic pain development, therefore there is a critical unmet need of safe, non-addictive, non-
invasive preventative treatment options that can be administered to MVC survivors in the 
aftermath of an injury. This study has the potential to benefit participants and future MVC 
survivors and improve pain and general health outcomes. The risks of taking Vitamin D are 
small.  Side effects from Vitamin D are rare, however, it is possible that over supplementation 
of Vitamin D may be associated with headache, loss of appetite, dry mouth, metallic taste, and 
nausea/vomiting.  
 
The risks to the subjects in experiencing these side effects are balanced against the potential 
for a new, safe, non-opioid preventative treatment option for chronic pain following MVC.  
Study Objectives 
 


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2.1  Primary Objective:  
1. Assess the feasibility of the RCT protocol by (a) calculating recruitment rate and 
participant retention, and (b) measuring the ability of Vitamin D administration to 
generate sustained increases in whole-blood Vitamin D concentrations (assessed 3 
months after MVC). 
2. To demonstrate the preliminary efficacy of Vitamin D administration per protocol on 
decreasing overall MSP severity during the 3 months following MVC, and reducing MSP 
outcome disparity between Blacks and Whites following MVC. 
 
2.2  Secondary Objectives: 
We will assess the effect of race and sex on treatment outcomes in secondary analyses. 
This will be accomplished using two analytic strategies. First, a sex X treatment 
interaction term (secondary analyses) will be entered into our statistical models to 
assess pain reduction in response to treatment. Second, a stratified analysis will be 
performed which will examine the influence of both sex and race on treatment effect on 
primary and secondary outcomes. Further, Secondary stratified analyses evaluate the 
influence of initial vitamin D level on treatment response. In addition, exploratory 
analyses on the relationship of vitamin D outcome and trajectory of pain as well as 
restricting analyses to participants with vitamin D deficiency at baseline will be 
performed. Secondary analyses will examine treatment effects adjusting for any 
baseline differences in psychosocial factors between treatment arms. 
 
2.3  Long-Term Aims Beyond the Present Proposal  
To use data collected to design and adequately power a larger-scale RCT assessing the 
efficacy of Vitamin D treatment in decreasing chronic pain in high-risk patients 
presenting for treatment in the aftermath of MVC and to reduce racial disparity in pain 
outcomes following MVC. 
Study Design 
3.1 General Design 
 
Figure 1: Overall Study Design  


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3.2 Study Overview  
Described the sequence of events in recruiting 90 patients in a multi-center randomized 
controlled trial. To assess a key primary outcome, we will enroll 50% white and 50% black 
MVC into the study. Each participant will be screened in based on a point of care Vitamin D 
test. This will be performed at the time of screening. Individuals with a Vitamin D level <100 
ng/ml will be enrolled. Patients will be randomized 1:1 to receive a single dose of 300,000 
IU of ergocalciferol versus placebo and followed for 3 months. At 3 months, patients will 
send a blood sample easily collected at home on a blood spot card to assess Vitamin D level 
3 months following injury which is a key feasibility primary outcome. 
 
Patients presenting to the ED within 24 hours of MVC (n=90, 45 non-Hispanic Black, and 
45 non-Hispanic White) will receive a single dose of study drug prior to ED discharge (1:1 
allocation 300,000 IU ergocalciferol or placebo). Prior to study drug administration, a 
baseline assessment will be performed (see below), and a fingerstick blood sample will be 
obtained to evaluate 25-hydroxyvitamin D level. Online survey follow-ups assessing 
primary and secondary outcomes and potential adverse events will be performed 3 
weeks, 6 weeks, and 3 months after ED enrollment by study RAs using web-based 
REDCap™ software. Participants will also complete brief “flash-surveys” at the 2-week, 4-
week, and 5-week timepoints using REDCap survey links. At 3 months, participants will 
also perform a fingerstick blood collection at home and mail the sample in a prepaid 
envelope to a lab to be processed to enable assessment of 3 month 25-hydroxyvitamin D 
concentration by treatment group. 
3.3 Posting on clinicaltrials.gov 
The study protocol will be published to clinicaltrials.gov prior to commencement of 
the trial. Results will be posted on clinicaltrials.gov when available.  
3.4 Primary Study Endpoints 
The primary endpoint of this study will examine the feasibility and efficacy of Vitamin 
D to improve overall MSP severity outcomes following motor vehicle collision in Blacks 
and Whites, as well as to reduce MSP outcome disparity between Blacks vs. Whites 
following MVC.  
 
Outcome to assess feasibility: 90 patients will be enrolled, randomized into one of 2 
treatment arms in a 1:1 ratio, and treated with study drug as a single-dose following motor 
vehicle collision with moderate to severe MSP within a 15-month period. Feasibility will also 
be measured by the ability to retain >80% of participants through 3-month follow-up, and 
achieve Vitamin D levels >20 ng/ml in 90% of treatment group at 3-month follow-up. In 
addition, will determine whether Vitamin D administration per protocol can raise Vitamin D 
concentration in treatment group >10 ng/ml above baseline. The concentration of Vitamin 


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D will be calculated before and after the treatment in each treatment arm to assess the 
response.  
 
Outcome to assess efficacy: Efficacy of Vitamin D will be measured by difference in pain 
severity in treatment arms versus control arms. Pain reduction between treatment groups 
will be assessed using patient-reported overall MSP scores (0-10 NRS) obtained at the ED, 3-
week, 6-week, and 3-month assessments. Estimates of efficacy will be obtained via 
repeated measures analysis using mixed effects models. Secondary Study Endpoints 
3.5 Primary Safety Endpoints 
To assess safety, adverse events will be tracked using REDCap through emailed/text-
messaged surveys during the drug treatment to assess side effects and safety profile of 
Vitamin D. Qualitative analysis of adverse events will be performed by investigative team.  
3.6 Inclusion Criteria 
1. ≥ 18 years and ≤ 65 years of age 
2. Admitted to ED within 24 hours of motor vehicle collision 
3. Plan to discharge to home from the emergency department 
4. Stated willingness to comply with all study procedures and availability for the duration 
of the study (with the exception of the blood draw sample collected in the ED, which is 
optional) 
5. Has a smartphone with continuous service >1 year 
6. Able to speak and read English 
7. Alert and oriented, and capable of engaging in informed consent 
8. Willing to take on-time dose of study medication (2 capsules of Vitamin D or placebo) 
9. Non-Hispanic white or non-Hispanic black 
10. Point of care Vitamin D level <100 ng/ml 
11. During ED admission pain severity must be at least 4/10 or higher 
3.7 Exclusion Criteria 
1. Substantial comorbid injury (e.g., long bone fracture) 
2. Pregnancy/breastfeeding 
3. Prisoner status 
4. Chronic daily opioid use prior to MVC (>20 mg oral daily morphine equivalents) 
5. Active psychosis, suicidal ideation, or homicidal ideation 
6. Plans for hospital admission 
7. Known chronic kidney disease, stage 4 or higher (GFR≤29) 
8. Intubated and sedated at time of enrollment 
9. Inability to provide informed consent (receipt of sedative, hypnotic agent making the 
patient non-decisional for consent) 
10. Known hypercalcemia 
11. Vitamin D supplements in excess of 800 IU daily 


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12. Any other history or condition that would, in the site investigator’s judgement, 
indicate that the patient would very likely be non-compliant with the study or 
unsuitable for the study (e.g., might interfere with the study, confound interpretation, 
or endanger patient) 
3.8 Subject Recruitment and Screening 
Prior to approaching the participant, medical history data will be reviewed for information 
pertaining to inclusion/exclusion criteria in section 3.6 and 3.7. If the participant is 
determined to be ineligible, the review will stop.  The purpose of assessing this 
information is to approach only those patients who are potentially eligible Record will be 
kept of patients who are screened but excluded and for what reason.  A HIPAA waiver will 
be requested to permit the review of medical record data for evident exclusion criteria 
prior to approaching a participant (this will reduce study burden on the study population).  
In participants who otherwise appear to be eligible for the study, the attending 
physician/medical record will be consulted to determine if admission is planned (most of 
the time this can be determined through chart review). Reasons for exclusion will be 
recorded. To be eligible for the study, during ED admission pain severity must be at least 
4/10 or higher). Participants will be approached by study personnel and will be offered 
participation. Participants will undergo informed consent with enrolling RAs in the ED. 
Participants will receive paper copies of their main study consent, HIPAA authorization, 
biospecimen collection and social security collection forms. Both the participant and 
consenter will open and review the documents. Because both the RA and the participant 
will have forms open, the participant will follow along on paper while the consenter 
explains each section. After reviewing the consent documents, if the potential participant 
is willing to participate, the consenter and participant both sign the consent forms and the 
RAs will enter their time and date of their signature in REDCap. Once all fields are 
complete, then a copy of the completed consents (Main Study Consent, HIPAA 
Authorization, Biospecimen Collection and SSN Form) are given to each the participant 
and the consenter. The consenter will then save a scanned copy of the forms to REDCap, 
the central and secure online study database.  
 
If participant refuses consent, data collected to that point will be retained to describe the 
proportion of MVC patients who were screened but refused to participate (we will 
maintain demographic information for audit purposes). Reason to refuse participation will 
be also documented and retained.  
 
If the participant is after 10 days following their last menstrual period, and is not on birth 
control, a urine pregnancy test will be performed prior to randomization. If the participant 
is found to be pregnant, they will be excluded from the study. Once participants are 
determined to meet full inclusion criteria and have no reason for exclusion, consented 
participants will be randomized and study drug will commence on enrollment in the study. 
Participants who are initially intubated may be eligible for the study, as long as they are 
extubated, alert, and oriented at the time of consent, enrollment and other eligibility 
criteria are met.  


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3.9 Early Withdrawal of Subjects 
3.9.1 When and How to Withdraw Subjects 
Participants may withdraw from the study at any point in time if they no longer wish to 
participate in the study. 
3.9.2 Data Collection and Follow-up for Withdrawn Subjects 
If the patient voluntarily withdraws from the study, outcome measures from completed 
timepoints will be collected and included in intention to treat analysis. If the patient is 
lost to follow-up and is unresponsive to more than 3 phone calls and 3 secure e-mails, 
the next of kin listed in the medical record will be contacted once to attempt to reach 
the participant. If this is not successful, then 1 final email will be sent to attempt to 
contact the consented participant.  
Study Drug  
4.1 Description 
The study drug is Vitamin D2 (ergocalciferol) 300,000 IU administered orally as 2 capsules 
comprising approximately 150,000 IU each. 
4.2 Treatment Regimen 
Within 24 hours of presenting to the ED for a MVC, and immediately following enrollment in 
this study, participants will be provided with study drug or placebo. The study drug and 
placebo will be manufactured and encapsulated by a 503b compounding pharmacy (i.e., 
Pharmacy Innovations), and will ship the study drug to the investigational pharmacy at each 
study site. Immediately following randomization, the IDS pharmacy will receive an email 
with the unblinded treatment allocation for the participant. The IDS at each site will 
dispense the appropriate study drug once they receive a prescription from the clinician at 
enrollment. Study medications (placebo or active) will be administered orally via a one-time 
dose that will be observed by the research personnel in the ER.  
4.3 Method for Assigning Subjects to Treatment Groups 
Once a potential subject has been successfully screened, does not meet any exclusion 
criteria, is willing to participate in the study, and signs informed consent, the participant will 
be randomized by the study site using a minimization algorithm stratified on race, sex, and 
pain score. Randomization of participants using minimization will be accomplished using a 
centralized, web-based, validated (compliant with FDA 21 CFR Part 11) service 
(randomize.net). In this algorithm, a new participant is sequentially assigned to a particular 
treatment group by taking into account the covariates of the current and previously 
randomized participants. To further optimize power in this small, pilot study to examine the 
effect of race, and achieve a main goal of this study, a 1:1 ratio of non-Hispanic Black and 
White Americans will be enrolled. Once enrollment reaches 45 in a given race strata (e.g., 
non-Hispanic Black), enrollment for that race will cease. All participants, investigators, study 


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personnel, and follow-up team members will be blinded to allocation and concealment will 
be maintained throughout the study. Only the investigational pharmacy and study 
statistician will be unblinded to the drug the participant is receiving. They will not reveal this 
to the patient care team, investigative team, or to the participant. Dosing schedule, route of 
administration, number of pills in each dose, and the appearance of the capsules will be 
identical among each group.    
4.4 Preparation and Administration of Study Drug 
Study medication Vitamin D2 and comparator, will be ordered and manufactured directly by 
a 503b compounding pharmacy (i.e., Pharmacy Innovations) and shipped to each site’s 
investigational drug pharmacy (IDS).  All medication will be stored in a climate-controlled 
storage area.  The containers will be labeled by the manufacturer and each IDS will receive 2 
bottles (active and placebo). The IDS will store and administer each dose, depending on the 
arm the participant is randomized into. Each participant will receive 2 capsules of 
indistinguishable active study drug or placebo.  
4.5 Subject Compliance Monitoring 
Administration of the study drug will be completed by ED nursing staff and will be 
documented in the medication administration record (MAR). Reasons for refusal will be 
documented in the MAR. If the participant does not receive study drug but is randomized, 
they will be excluded from subsequent analysis.  
4.6 Prior and Concomitant Therapy 
Prior and concomitant analgesic and anti-inflammatory treatments will be collected on 
enrollment, discharge from the hospital through data extraction, and at each REDCap 
survey follow-up assessment. Analgesic medications as would be normally prescribed are 
permitted throughout this study including anti-inflammatory agents. Consumption of 
medication will be tracked and addressed in secondary analyses.  
4.7 Packaging 
Study drug and inert placebo will be shipped from supplier in bulk containers and stored in 
the investigational drug pharmacy. 
4.8 Blinding of Study Drug (if applicable) 
Only the investigational drug services and unaffiliated staff will know the contents of the 
capsules. The study drugs and comparator will be packaged in identical capsules and will be 
indistinguishable. Each participant will be assigned to a treatment arm using randomize.net. 
Randomization will be accomplished via randomize.net. A Randomization ID will be 
generated that corresponds to the treatment. Only the IDS will dispense the study drug 
maintaining strict blinding.    


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4.9 Receiving, Storage, Dispensing and Return 
4.9.1 Receipt of Drug Supplies 
The drug supplier will ship the study drug and comparator to the Investigation Drug 
Pharmacy. Once the study drug arrives, receipt of the study drug will be performed. A 
drug receipt log will be completed and signed by the person accepting the shipment. 
Each site will develop their own process for maintaining a log of drug administration. 
The designated study staff will count and verify that the shipment contains all the items 
noted in the shipment inventory supplied at the time of shipment.  Any damaged or 
unusable study drug in a given shipment (active drug or comparator) will be 
documented in the study files.   
4.9.2 Storage 
Drug will be stored at 77 degrees Fahrenheit with excursions permitted from 59-86 
degrees Fahrenheit at the investigational drug pharmacy. At each site, it will be kept in a 
climate-controlled room. The drug will not be frozen. There is no requirement for the 
drug to be shielded from light or any other special requirements.  
4.9.3 Dispensing of Study Drug 
The study drug will be dispensed by ED nursing staff. Study drug reconciliation will be 
performed at the conclusion of the study. This reconciliation will be logged on the drug 
accountability form and signed and dated by the study team. This log will be kept by the 
site investigational drug pharmacy and via the REDCap data collection software being 
used in this study.   
4.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
consumed, and drug remaining.  This reconciliation will be logged on the drug 
reconciliation form, signed and dated.  Any discrepancies noted will be investigated, 
resolved, and documented prior to return or destruction of unused study drug.  Drug 
destroyed on site will be documented in the study files. 
Study Procedures 
5.1 Enrollment Procedures 
This first visit will take place upon admission to the hospital following MVC within 24 hours 
of the collision. Patients who meet inclusion criteria/exclusion criteria based on a review of 
the electronic medical record by research assistants, participants will be approached for 
participation. If the patient is interested in participating, they will then undergo informed 
consent. At this point in time, the participants will undergo baseline assessments 
(administered through REDCap) and collections of point of care Vitamin D levels with blood 
spot card. The participants will also have the option to consent to collect additional blood 
during a standard of care procedure while in the ED. The study would collect an EDTA tube, 


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a sodium heparin tube, and PAX gene RNA and DNA tubes. Patients with a Vitamin D level 
<100 ng/ml, will then take the baseline questionnaire. After all baseline data is collected, 
participants will be randomized and then administered appropriate study medication 
(Vitamin D or placebo). This administration will be documented in the MAR. Patients will 
be given a paper copy of their consent. Upon discharge of the patient, the patient will be 
given supplies to perform a home fingerstick blood draw (similar to one collected in the ED 
for baseline) and blotting on a blood spot card, which will occur at the 3-month timepoint.  
 
 
Medical record information abstracted at time of admission will include information 
related to patient past medical history and initial motor vehicle collision care, and 
medication use prior to admission and prior to enrollment. Laboratory values relevant to 
patient renal and hepatic function will also be recorded (if obtained) along with any 
toxicology labs obtained by the primary treating team. 
 
Demographic and phenotypic data will be collected at this time. Patients will be asked to 
report demographic information including age, sex, ethnicity, education level, income 
level, and marital status. In addition, patients will be administered an enrollment survey 
which will collect domains important to the pain experience. These are listed in table 2. All 
patient information will be recorded by a trained research assistant or the patient via 
direct entry. We will assess treatment expectation using a modified survey that uses Likert 
scales prior randomization. In addition, we will administer weekly surveys of pain severity 
and to assess whether adverse events are experienced weekly through 6 weeks (these 
brief surveys will be sent at 2 weeks, 4 weeks and 5 weeks). Adverse events will also be 
monitored at 3 weeks, 6 weeks, and 3 months following administration of study drug. 
Table 2. Assessments by domain at each timepoint 
Domain 
Measure 
D1 3W 6W 3M 
Demographic 
information 
Age, sex, gender, race/ethnicity, education, income, 
marital status 
● 
 
 
 
Pre-MVC 
Pain catastrophizing scale26,  PROMIS Item Bank v1.0 - 
Emotional Distress – Anxiety27, PROMIS Item Bank v1.0 
- Emotional Distress - Depression27, Anxiety Sensitivity 
Index51 
● 
● 
● 
● 
Traumatic Event 
Details of Traumatic Event, Concussion, Traumatic 
Brain Injury,  Life events checklist28  
● 
 
 
 
MVC Injury Severity 
Abbreviated injury scale29 
● 
 
 
 
Pain 
Numeric Rating Scale, †RPS30, PROMIS Short Form v1.0 
- Pain Interference 4a31, PROMIS Scale v2.0 - 
Neuropathic Pain Quality 5a32,  PROMIS Scale  
v2.0-Nociceptive Pain Quality 5a 
● 
● 
● 
● 
Somatic Symptoms 
Pennebaker Inventory of Limbic Languidness52 
● 
● 
● 
● 
Global Mental and 
Physical Health 
PROMIS Scale v1.2 - Global Mental 2a33, PROMIS Scale 
v1.2 - Global Physical 2a33,34 
● 
● 
● 
● 


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At the time of enrollment, blood for DNA will be collected using a PAXgene DNA storage tube (8.5cc). 
These samples will be stored at -70 oC or below for future testing. Blood for RNA will be collected 
using a PAXgene RNA storage tube (2.5cc).  These samples will be stored at -70 oC or below for future 
testing. Blood for immune profiling will be collected in sodium heparin tubes (16cc).  Whole blood 
collected from sodium heparin tubes will be aliquoted into SmartTubes which allow storage for later 
processing by mass cytometric methods. Additional aliquots from these tubes will used to assess 
adaptive and innate immune function in vitro.  Blood for lipidomics, vitamin D level and protein 
expression analysis will be obtained via EDTA tubes containing K2EDTA for sample anticoagulation 
(8cc).  Plasma will be separated from the cells by centrifuging the collection tube for 10 minutes at 
2000 rpm at 25 °C, within two to 48 hours of collection.  Plasma will be stored in 100-250 µL aliquots 
in plastic microcentrifuge tubes at -70 °C or below for future testing. Total amount of blood collected 
via venipuncture will be 35-36cc. A drop of blood will be applied to a dried blood spot cards for 
Vitamin D testing. 
5.2 Emergency Department Medication Administration 
The single dose administration will be provided in an observed fashion in the emergency 
department. This administration will be recorded in the patient’s electronic medical record 
in the medication administration record (MAR).  
5.3 Data Extraction 
Medical record information abstracted after discharge will include information on the 
patient's health status and care during hospitalization and at the time of discharge.  This 
information will include MVC characteristics, medications taken during emergency 
department admission, and discharge medications. All data extraction will be stored in 
REDCap. 
5.4 Text messaged or e-mailed outpatient Weekly Pain and Compliance 
Assessments  
Brief, weekly assessments of pain severity (0-10 NRS), and review of any AEs over the past 
week  will occur via e-mailed surveys administered through our secure study database 
REDCap. Patients will receive text messages from the Data Coordinating Center based on a 
predetermined schedule based on progress, using the secure study phone number. If 
Anxiety/Depressive 
Symptoms 
PROMIS Item Bank v1.0 - Emotional Distress – 
Anxiety27, PROMIS Item Bank v1.0 - Emotional Distress 
- Depression27 
● 
● 
● 
● 
Posttraumatic stress 
symptoms 
PTSD Symptom Severity index-interview for DSM-535,  
Peritraumatic Distress Inventory items (PDI)53 
● 
● 
● 
● 
Dissociative Symptoms Michigan Critical Events Perception Scale36 
● 
 
 
 
Analgesic Medication 
Use 
Daily milligram morphine equivalents, non-opioid 
analgesic use, Date of opioid cessation (first day in 
three consecutive where patient took no opioids)37. 
● 
● 
● 
● 
Substance abuse 
PROMIS Short Form v1.0 - Severity of Substance Use 
(Past 30 days) 7a38 
● 
● 
● 
● 
Patient satisfaction with 
treatment 
Patient Global Impression of Change39 
 
● 
● 
● 


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patients are not able to respond via text messaging or e-mail, they will be called by 
investigative team. This brief survey will be administered at 2 weeks, 4 weeks, and 5 
weeks.  
5.5 3- and 6-week assessment 
The goal of this assessment is to perform a comprehensive phenotypic follow-up and a 
questionnaire assessing domains listed in table 2 will be assessed. Outcome assessments 
will be performed via structured survey either via a web-based Redcap survey emailed to 
their on-file email address or via telephone. Multiple methods of contacting participants 
are involved to best meet the needs of each individual participant. Patients will receive 
automated REDCap email reminders. Participants will also receive text reminders based on 
a predetermined schedule based on progress. If patients are not able to respond via text 
messaging or e-mail, they will be called by investigative team. 
5.6 3-month assessment 
The goal of this assessment is to perform a comprehensive phenotypic follow-up and a 
questionnaire assessing domains listed in table 2 will be assessed. Outcome assessments 
will be performed via structured survey either via a web-based Redcap survey emailed to 
their on-file email address or via telephone. Multiple methods of contacting participants 
are involved to best meet the needs of each individual participant. Patients will receive 
automated REDCap email reminders, and text message reminders sent on a predetermined 
schedule based on progress. If patients are not able to respond via text messaging or e-
mail, they will be called by investigative team. In addition, the patient will obtain a blood 
sample blotted onto a blood spot care acquired via a fingerstick at the 3-month mark of 
their study participation (achieved with a sterile lancet mailed to the participant at the 2-
month timepoint of study participation). The completed sample card will be mailed via a 
self-addressed envelope to the central processing laboratory. All materials and education 
to conduct this blood draw will be mailed to participants and patients will be reminded this 
procedure at the 3-month follow-up. If the participant loses the materials, they will be re-
shipped to the participant from the data coordinating center. 
Statistical Plan 
6.1 Outcome definitions/Analysis plan/Power calculation 
Assess the feasibility of the RCT protocol by (a) calculating recruitment rate and participant 
retention, and (b) measuring the ability of Vitamin D administration to generate sustained 
increases in whole-blood Vitamin D concentrations (assessed 3 months after MVC). 
 
Outcome definitions for Feasibility will be determined by the ability of the study team to: 
recruit 90 patients into the trial over the 15-month recruitment period, retain >80% of 
participants through 3-month follow-up, and achieve Vitamin D levels >20 ng/ml in 90% of 
treatment group at 3-month follow-up. In addition, will determine whether Vitamin D 


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administration per protocol can raise Vitamin D concentration in treatment group > 
10ng/ml above baseline.  
 
Analyses: Feasibility analyses will be performed using descriptive statistics. To assess 
Vitamin D increase according to treatment group, paired t-test will used. 
 
Power: Based on our previous Vitamin D trial and other work,40-45 we estimate that 
observed follow-up will be ~80%. With n=90 sample, this will permit follow-up rates 
estimates at 3 months with 95% CI ± 8.3%. This will permit assessment of follow-up 
feasibility and necessary sample size for an R01 RCT, if pilot results warrant. In addition, 
based on our previous Vitamin D trial, assuming 80% retention and Vitamin D concentration 
standard deviation of 4ng/ml, we will have >99% power to detect a change of 10 ng/ml in 
Vitamin D level in the treatment group. 
 
Assess preliminary efficacy of Vitamin D administration per protocol to (a) decrease overall 
MSP severity during the 3 months following MVC, and (b) reduce MSP outcome disparity 
between Blacks vs. Whites following MVC. 
 
Outcome Definitions for Pain Reduction between treatment groups will be assessed using 
patient-reported overall MSP scores (0-10 NRS) obtained at the ED, 3-week, 6-week, and 3-
month assessments. NRS scores are valid measures of pain assessment.46,47 
 
Analysis plan Overall efficacy (a) will 
be addressed by evaluating for 
evidence that Vitamin D administration 
per protocol vs. placebo decreases 
overall MSP scores across study 
timepoints. The effect of the 
intervention on overall pain over time 
will be assessed by evaluating the 
coefficient for treatment group (1) in 
the model: Pij = 0 + 0i + 1Treatmenti 
+ 2Racei + 3(Treatment × Race) + ij, 
where Pij is the pain score for the ith 
individual at time point j, ’s denotes 
fixed effects, 0i is the random 
intercept for the ith individual and  
corresponds to random errors. 
Narrowing of racial disparity will be 
addressed by evaluating the 
interaction between race and treatment (3 in model above). Specifically, as described 
above we will assess whether Vitamin D has greater effect on pain outcomes over time in 
Blacks than Whites. All analyses will be evaluated on the basis of intention to treat. Prior to 
Figure 2. Plot demonstrating power to detect a main 
effect (β1, black lines) and interaction (β3, blue lines) 
across a range of sample sizes, at three effect sizes 
estimated using simulation data generated from previous 
studies. Vertical red line indicates sample size proposed 
here (n=90). This demonstrates the power to assess Aim 
2a (black) and 2b (blue).  


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data un-blinding, the study statistician will perform a blind review of the data in which 
statistical models will be developed and tested using dummy (computer-generated) 
treatment assignments. This is to ensure important covariates are added to the model prior 
to un-blinding to eliminate any bias of model covariate selection on results. After un-
blinding the data, we will use appropriately specified linear contrasts of model parameters 
to estimate mean differences between participants treated with Vitamin D and placebo and 
95% confidence intervals.  
 
Power Estimates of power were derived using a Monte Carlo simulation based on 
parameter estimates from our observational data of MVC survivors using R (v. 4.0.248); and 
the simr package (v. 1.0.549). The power across a range of effect sizes for the main effect (a) 
is shown in Figure 2. These data and analysis must be seen as general estimates given that 
we lack intervention data for this population/condition.  
 
Secondary Analyses: 
Similar models as for the primary outcome will be fit for both the Brief Pain Inventory 
and the SF-12 Mental and Physical Component Scale Scores. 
 
Sex as a biological variable (SABV) will be examined in treatment response including 
sex-by treatment interaction terms in the mixed effect model specified above and 
exploring sex differences in therapeutic response to Vitamin D and n-3 PUFAs. 
 
General mental and physical health will be assessed using SF-12 physical and mental 
component scores (PCS and MCS) and the impact on physical and mental functioning 
will be determined in each of the treatment groups. A clinically important reduction in 
SF-12 PCS and MCS ranges between 2.5-4.550; therefore, a reduction of ≥ 4.5 will be 
considered a clinically significant improvement MCS/PCS.  
 
Brief Pain Inventory: We will also use multivariable analysis to determine the role of n-3 
PUFA/Vitamin D supplementation in pain interference using composite and individual 
measures of the Brief Pain Inventory. 
 
6.2 Subject Population(s) for Analysis 
We will examine effect of Vitamin D on pain outcomes using an intention to treat paradigm. 
Participants will be analyzed in the group in which they are randomized. 
Safety and Adverse Events 
7.1 Definitions 
 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  


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• Unexpected in nature, severity, or frequency (i.e., not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators 
brochure, etc.). 
• Related or possibly related to participation in the research (i.e., possibly related 
means there is a reasonable possibility that the incident experience, or outcome may 
have been caused by the procedures involved in the research). 
• Serious (as defined below) “Serious” is different than “severe” as reported in the CTC 
criteria that applies a grade to the AE. 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens 
in severity during the course of the study. Intercurrent illnesses or injuries should be 
regarded as adverse events.  Abnormal results of diagnostic procedures are considered to 
be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but 
are clearly of major clinical significance.   They may jeopardize the subject, and may 
require intervention to prevent one of the other serious outcomes noted above.  For 
example, drug overdose or abuse, a seizure that did not result in in-patient 
hospitalization, or intensive treatment of bronchospasm in an emergency department 
would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as 
the period from the initiation of any study procedures to the end of the study treatment 


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follow-up.  For this study, the study treatment follow-up is defined as 30 days following 
the last administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities 
that meet the definition of an adverse event must also be recorded and documented as 
an adverse event.  
 
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At 
the last scheduled survey, the investigator should instruct each subject to report any 
subsequent event(s) that the subject, or the subject’s personal physician, believes might 
reasonably be related to participation in this study.  
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed 
otherwise in this protocol.  Any condition responsible for surgery should be documented 
as an adverse event if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or diagnostic 
and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement 
for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator. 
7.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events 
by specific questioning and, as appropriate, by examination.  Information on all adverse 
events should be recorded immediately in the source document, and also in the appropriate 


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adverse event module of the case report form (CRF).  All clearly related signs, symptoms, 
and abnormal diagnostic procedures results should be recorded in the source document, 
though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course 
of each event should be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  Serious adverse 
events that are still ongoing at the end of the study period must be followed up to 
determine the final outcome.  Any serious adverse event that occurs after the study period 
and is considered to be possibly related to the study treatment or study participation should 
be recorded and reported immediately. 
7.3 Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor will conform to the adverse event reporting 
timelines, formats and requirements of the various entities to which they are responsible, 
but at a minimum those events that must be reported are those that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
(See definitions, section 8.1).   
If the report is supplied as a narrative, the minimum necessary information to be 
provided at the time of the initial report includes: 
 
• Study identifier 
• Study Center 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• The reason why the event is classified as 
serious 
• Investigator assessment of the association 
between the event and study treatment 
 
7.3.1 Investigator reporting 
7.3.1.1 Unanticipated Problems, Severe Adverse Events 
Any study-related unanticipated problem posing risk of harm to subjects or others, and 
any type of serious adverse event, must be reported to the study data coordinating 
center by telephone within 24 hours of the event.  To report such events, a Serious 
Adverse Event (SAE) form must be completed by the investigator and faxed/emailed to 
the data coordinating center within 24 hours.  The investigator will keep a copy of this 
SAE form on file at the study site.   
 
Within the following 48 hours, the investigator must provide further information on the 
serious adverse event or the unanticipated problem in the form of a written narrative.  
This should include a copy of the completed Serious Adverse Event form, and any other 


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diagnostic information that will assist the understanding of the event.  Significant new 
information on ongoing serious adverse events should be provided promptly to the data 
coordinating center.  
7.3.1.2 Other Reportable Events 
For clinical drug trials, the following events are also reportable to the UNC IRB: 
• Any adverse experience that, even without detailed analysis, represents a serious 
unexpected adverse event that is rare in the absence of drug exposure (such as 
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 
• Any adverse event that would cause the sponsor to modify the investigators 
brochure, protocol or informed consent form, or would prompt other action by 
the IRB to assure protection of human subjects. 
• Information that indicates a change to the risks or potential benefits of the 
research, in terms of severity or frequency. For example:  
– An interim analysis indicates that participants have a lower rate of 
response to treatment than initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or 
more frequent than initially expected. 
– A paper is published from another study that shows that an arm of your 
research study is of no therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, or 
biologic used in a research protocol. 
• Breach of confidentiality 
• Change to the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research participant. 
• Incarceration of a participant when the research was not previously approved 
under Subpart C and the investigator believes it is in the best interest of the 
subject to remain on the study. 
• Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more 
participants at increased risk, or affects the rights or welfare of subjects. 
• For reportable deaths, the initial submission to the UNC IRB may be made by 
contacting the IRB Director or Associate Director. The AE/Unanticipated Problem 
Form is required as a follow up to the initial submission. 
7.3.1.3 External Site Reporting  
Investigators who are not UNC faculty or affiliated with a UNC research site are 
responsible for safety reporting to their local IRB.  Investigators are responsible for 
complying with their local IRB’s reporting requirements, though must submit the 
required reports to their IRB no later than 10 working days.  Copies of each report and 
documentation of IRB notification and receipt will be kept in the investigator’s study file. 


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7.4 Unblinding Procedures 
Unblinding the group in which the patient is randomized will only occur in exceptional 
circumstances when the knowledge of treatment is essential for the management of an 
individual patient. In emergency situations (e.g., anaphylaxis) the principal investigator may 
contact IDS to have the identity of the patient’s treatment drug revealed to help manage the 
patient more effectively. If this occurs, the unblinding procedure will be documented in the 
patient’s source documents. 
7.5 Stopping Rules  
The entire trial will stop if 3 or more patients have severe adverse events of grade 3 (severe) 
or higher severity per the CTCAE scale that is related or possibly related to study participation, 
or any investigator judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, or good clinical practice. Patients who decline 
further participation and patients experiencing adverse effects that in the opinion of study 
investigators indicate that study drug should be stopped will be discontinued from study 
medication. Criteria for stopping the study trial among individual participants for review are 
shown in Appendix 1. 
7.6 Medical Monitoring 
Safety Monitoring Plan: Overall safety oversight will be the responsibility of the data 
coordinating center PIs Mauck and McLean (DCC PIs). The DCC PIs will monitor study and will 
communicate with the independent medical monitor with study status if adverse events 
occur. 
 
Data Safety Monitoring Board (DSMB):  
The NC TraCS DSMB Monitoring 
board will serve as the 
independent monitoring board for 
this trial. They will review and 
approve the study protocol, and 
will meet quarterly to review study 
progress (reports of enrollment, 
adverse events listed by type and 
severity will be generated by the 
study statistician and will be 
reported by treatment type 
(Vitamin D or placebo) once 
greater than 4 patients are 
enrolled in the study, and will again review the data at study conclusion. They will also review 
serious adverse events as they occur, and determine whether the adverse events change the 
risk of the study. Monitoring the study (across one or more study sites) is considerably 
facilitated by the use of a single electronic database which can be reviewed by the network PI, 
Serious AE 
Death, Life threatening reaction 
Inpatient hospitalization prolonged, or 
rehospitalization. Persistent or significant 
disability/incapacity 
Congenital anomaly/birth defect 
Represents other significant hazards or 
potentially serious harm to research 
subjects (similar to “important medical 
event”) 
Expected AE Known potential effect of the drug (based 
on drug description information from 
manufacturer) or disease process 


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study site PI(s), and other investigators.  The DCC PI will monitor for adverse events that change 
study risk level and this will be communicated with the independent medical monitor if needed.  
Adverse events at individual study sites will also be monitored by the site PI.  If an adverse 
event occurs which changes the study risk level, the DCC PI will immediately report this event to 
the DCC IRB (UNC IRB), inform the site PI(s), and oversee the process of modifying the study at 
the study site(s) as appropriate to address the change in risk.  The DCC PI will also provide 
annual reports summarizing AE data to the data coordinating center IRB (UNC IRB) and any 
other requesting IRB.  The site PI(s) will oversee patient safety at their site, with delegation of 
responsibilities to other investigators and designated study personnel as appropriate.  The DCC 
PI, together with their study site teams, will ensure that all entry criteria are met prior to the 
initiation of the protocol, and that all study procedures and reporting of adverse events are 
performed according to the protocol.  Serious adverse events (SAE's) will be monitored by the 
study site investigative teams in real time throughout the trial.  
  
Patient monitoring: An adverse event is any physical or clinical change experienced by 
the patient.  This includes the onset of new symptoms and the exacerbation of pre-
existing conditions.  Adverse event assessments will be performed according to the 
following schedule: 
 
Adverse event monitoring after discharge from ED: Adverse events will be assessed at 
each patient contact (telephone or text-messaged/emailed survey), which will occur 
weekly for 6 weeks, then again at 3 months. 
 
Additional reporting: In addition to receiving these regular side effect assessments, 
patients will be given contact information to reach the study team at the DCC, as well as 
telephone and pager numbers for individuals at the study site, and will be instructed to 
call these numbers if they experience any changes in their health status or if they have 
questions regarding the study medication. 
 
Category definitions for adverse events are shown in Table 3.  An electronic adverse event form 
will be completed for all unanticipated AEs.  The severity of the AE will be assessed a CTCAE 
grade will be recorded for each.  An 
investigator will also assess the relationship 
of any adverse event to study medication or 
procedures.  Severity assessments will be 
performed using the Common Toxicity 
Criteria (http://ctep.cancer.gov/).  The time 
table for reporting serious and other adverse 
events is shown in Appendix 1. 
Unanticipated problems involving risks to participants or others, defined as any incident, 
experience or outcome that is both unexpected and related or possibly related to the research, 
will be reported to the IRB.  Unanticipated problems that are serious adverse events will be 
reported to the IRB within 1 week of the investigator becoming aware of the event.  Any other 
Table 3. Time table for reporting 
unanticipated adverse events. 
 
Unanticipated 
Serious AE 
One week 
Not Serious 
AE/other 
Two weeks 


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unanticipated problem will be reported to the IRB within 2 weeks of the investigator becoming 
aware of the problem. The study team will report all serious unanticipated adverse events to 
the DCC PI immediately, and will review all non-serious unanticipated adverse events with the 
PI within 24 hours.   
 
Patients with adverse events will be monitored with relevant clinical assessments (and 
laboratory tests if necessary) as determined by an investigator in collaboration with the 
patient’s care team.  All adverse events will be followed to satisfactory resolution or 
stabilization of the event(s).  Any actions taken and follow-up results will be recorded on the 
appropriate AE form and given a CTCAE grade. 
 
Appendix 1 describes the adverse event grading scale and management guidelines for potential 
adverse events related to the study drugs. This chart covers a number of common adverse 
effects, but will not be comprehensive.  As other situations are encountered and managed by 
the study team, this decision rule chart will be updated and expanded so that it remains current 
and inclusive.   
 
Summary information regarding adverse events will be provided to the IRB at the time of 
annual IRB renewal.  As described below, medical monitor reports from both DCC and 
Independent Medical Monitor will also be submitted to the UNC IRB on a quarterly basis.  
Criteria for stopping the study trial among all participants for review are shown in Appendix 1.  
 
Patients experiencing adverse effects that in the opinion of the investigators merit drug dosage 
adjustment will have their dosage advanced more slowly, or the next dose reduced or held as 
appropriate.  If necessary, patients will be maintained on a lower dose, or their dose will be re-
advanced depending on the nature of the side effect(s).  Patients who decline further 
participation and patients experiencing adverse effects that in the opinion of study 
investigators indicate that study drug should be stopped will be discontinued from study 
medication. 
 
Independent Medical Monitor: To handle individual problems that may require communication 
directly with physician caring for the patient, an independent Medical Monitor will become 
involved. This is to avoid any conflicts of interest that may arise with data Handling and record 
keeping. 
7.7 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 


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• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts will be made to obtain permission to collect at least vital status (i.e., that the 
subject is alive) at the end of their scheduled study period. 
7.8 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Examples of these original documents, and 
data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical trial. 
7.9 Case Report Forms (as applicable) 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF will be recorded in REDCap.  All missing data will be noted.  If a 
space on the CRF is left blank because the procedure was not done or the question was not 
asked, “N/D” will be written.  If the item is not applicable to the individual case, “N/A” will 
be written.  All entries will be entered electronically in REDCap database.  If any entry error 
has been made, to correct such an error, a single straight line will be drawn through the 
incorrect entry and the correct data will be entered above it.  All such changes will be 
initialed and dated.   For clarification of illegible or uncertain entries, the clarification above 
the item will be printed initialed and dated. 
7.10 Records Retention 
Essential study documents (consents, paper questionnaires, screening forms) will be 
maintained for the duration of the IND. Data will not be de-identified/unlinked from original 
dataset to preserve the ability to contact patients should any unknown adverse events become 
known following the study. This data will be stored on a password encrypted server (REDCap at 
UNC). 
Study Monitoring, Auditing, and Inspecting 
8.1 Study Monitoring Plan 
This study will be monitored according to the monitoring plan described above.  The 
Investigator will also ensure that the monitor or other compliance or quality assurance reviewer 


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is given access to all the above noted study-related documents and study related facilities (e.g., 
pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
8.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance 
groups of all study related documents (e.g., source documents, regulatory documents, data 
collection instruments, study data etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
Risk based monitoring plan will include study site visits (may be virtual via secure video 
conferencing link) from study DCC after 2 and 10 enrolled patients at sites once they become 
active.  
 
Participation as an investigator in this study implies acceptance of potential inspection by 
regulatory authorities and applicable University compliance and quality assurance offices. 
Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB concerning 
the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the sponsor before commencement of this study.  The investigator should 
provide a list of EC/IRB members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in 
this study.  See attached copy of the Subject Informed Consent Form.  This consent form will be 
submitted with the protocol for review and approval by the EC/IRB for the study.  The formal 
consent of a subject, using the EC/IRB-approved consent form, must be obtained before that 
subject undergoes any study procedure.  The consent form must be signed by the subject or 
legally acceptable surrogate, and the investigator-designated research professional obtaining 
the consent.  
Study Finances 
10.1 Funding Source 
This study is funded by the National Institute of Health (NIMHD) and the UNC Department of 
Anesthesiology, and the Institute for Trauma Recovery.  


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10.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study 
sponsor prior to participation in this study.  All UNC investigators will follow the University 
conflict of interest policy. 
10.3 Subject Stipends or Payments 
To compensate participants for their time for completing follow-up interviews, we will offer 
patients $40 for the enrollment interview and $10 for patients who consent to the optional 
blood draw. Participants will be contacted at week 2, week 4 and 5 for brief surveys and will be 
compensated $20 for each week’s survey completion (for a total of 60 dollars for these 
assessments). At 3 weeks, participants will be compensated $50 for survey completion, at 6 
weeks they will receive $55 for survey completion, and at the 3 months visit they will be 
compensated $60 for survey completion and $40 for returning a blood spot card collected at 
home and mailed to the laboratory processing facility. The maximum total compensation for 
completing all study tasks will be $315. All payments will be made via electronic gift card(s) sent 
to the patient’s email within the week after a study activity is completed.  
Publication Plan 
Principal investigator, in coordination with investigative team will determine the publication 
plan as appropriate on an ongoing basis. We will make every effort to publish study results 
within 1 year of database completion. The results will be published on ClinicalTrials.gov website 
within 1 year of study completion per regulation. 
Data Management Plan 
REDCap will be used as our research database and is a secure, widely-used system for recording 
study information.  Access to enter data and view patient information will be password 
protected and accessed only by study personnel. At the time of enrollment or subsequent 
follow-up interview, data will be directly entered into REDCap. A codebook for the dataset will 
be compiled and saved along with the completed dataset. Our laboratory data manager will be 
responsible for assembling the final de-identified dataset and distribution to the study 
statistician for analysis. Completeness of the dataset will be determined as a percentage of 
non-missing data. When possible, reasons for missing values will be recorded (e.g., not 
applicable, refused to answer). Each research assistant that enters data in the system will be 
trained on mock patients and coding of patient responses will be checked. Data will be 
recorded by study sites directly into REDCap. Any discrepancies in coding will be handled by 
direct communication with study personnel at each study site.  
 
 


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Appendices  
14.1 Appendix 1: Adverse Event Monitoring and Stopping Rules Table 


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AE 
Relatedness 
CTCAE Grade 
1 
2 
3 
4 
5 
Back Pain 
 
Mild Pain 
Moderate pain; limiting 
instrumental ADL 
Severe pain; limiting self 
care ADL 
 
 
Possible 
O 
O 
O 
Probable 
O 
O 
SI 
Definite 
O 
SI 
SI 
Gastrointestinal pain 
 
Mild Pain 
Moderate pain; limiting 
instrumental ADL 
Severe pain; limiting self 
care ADL 
 
 
Possible 
O 
O 
O 
Probable 
O 
O 
SI 
Definite 
O 
SI 
SI 
Belching (or 
Flatulence) 
 
 
Mild symptoms; 
intervention not 
indicated 
Moderate; persistent; 
psychosocial sequelae 
 
 
 
Possible 
O 
O 
Probable 
O 
O 
Definite 
O 
SI 
Rash (maculo-
papular?) 
 
Macules/papules 
covering 
<10% BSA with or 
without 
symptoms (e.g., 
pruritus, 
burning, tightness) 
Macules/papules 
covering 10 - 30% BSA 
with or without 
symptoms (e.g., 
pruritus, burning, 
tightness); limiting 
instrumental ADL 
Macules/papules covering 
>30% BSA with or without 
associated symptoms; 
limiting self care ADL 
 
 
Possible 
O 
O 
O 
Probable 
O 
O 
SI 
Definite 
O 
SI 
SI 
Dysgeusia 
 
 
 
 
 
Altered taste but no 
change in diet 
Altered taste with 
change in diet 
(e.g., oral 
supplements); 
noxious or unpleasant 
taste; 
loss of taste 
 
 
 
Possible 
O 
O 
Probable 
O 
SI 
Definite 
O 
SI 
Bruising 
 
Localized or in a 
dependent area 
Generalized 
 
 
 
Possible 
O 
O 
Probable 
O 
O 
Definite 
O 
SI 
Hematoma 
 
Mild symptoms; 
intervention not 
indicated 
Minimally invasive 
evacuation or 
aspiration indicated 
Transfusion, radiologic, 
endoscopic, or elective 
operative intervention 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Possible 
O 
O 
SI 
SI 
 
Probable 
O 
SI 
SI 
SI 
 
Definite 
O 
SI 
SI 
SI 
 


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Atrial fibrillation 
 
Asymptomatic, 
intervention not 
indicated 
Non-urgent medical 
intervention 
indicated 
Symptomatic and 
incompletely controlled 
medically, or controlled with 
device (e.g., pacemaker), or 
ablation 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Possible 
O 
SI 
SI 
SI 
 
Probable 
O 
SI 
SI 
SI 
 
Definite 
O 
SI 
SI 
SI 
 
Atrial flutter 
 
Asymptomatic, 
intervention not 
indicated 
Non-urgent medical 
intervention 
indicated 
Symptomatic and 
incompletely 
controlled medically, or 
controlled with device (e.g., 
pacemaker), or ablation 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Possible 
O 
SI 
SI 
SI 
 
Probable 
O 
SI 
SI 
SI 
 
Definite 
O 
SI 
SI 
SI 
 
Alanine 
aminotransferase 
(ALT) 
increased 
 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
 
Possible 
O 
SI 
SI 
SI 
Probable 
O 
SI 
SI 
SI 
Definite 
O 
SI 
SI 
SI 
Aspartate 
aminotransferase 
increased 
 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
 
 
 
 
Possible 
O 
SI 
SI 
SI 
Probable 
O 
SI 
SI 
SI 
Definite 
O 
SI 
SI 
SI 
Cholesterol high 
 
>ULN - 300 mg/dL; 
>ULN - 7.75 mmol/L 
>300 - 400 mg/dL; 
>7.75 - 10.34 mmol/ 
>400 - 500 mg/dL; >10.34 - 
12.92 mmol/L 
>500 mg/dL; >12.92 
mmol/L 
 
 
 
Possible 
O 
O 
O 
SI 
Probable 
O 
O 
SI 
SI 
Definite 
O 
O 
SI 
SI 
Chills 
 
Mild sensation of 
cold; shivering; 
chattering of teeth 
Moderate tremor of the 
entire body; narcotics 
indicated 
Severe or prolonged, not 
responsive to narcotics 
 
 
Possible 
O 
RD 
SI 
Probable 
O 
SI 
SI 
Definite 
O 
SI 
SI 
Fever 
 
38-39ºC 
>39-40ºC 
>40ºC for <24 hours 
>40ºC for >24 hours 
Death 
Possible 
O 
O 
SI 
SI 
 
Probable 
SI 
SI 
SI 
SI 
 
Definite 
SI 
SI 
SI 
SI 
 
Criteria for stopping entire trial for review: The entire trial will stop if any investigator judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, or good clinical practice. 
Possible = The AE may be related to the intervention 
Probable = The AE is likely related to the intervention 
Definite = The AE is clearly related to the intervention 
*O = observe; SI = stop individual; ST = stop trial 
*Grades defined by NCI CTCAEv5.0 


VENTURE Trial  
 
 
 
 
 
 
 
 
 
Page 33 
Version: 1 
CONFIDENTIAL 
 
*This chart covers many common adverse effects, but will not be comprehensive.  This chart is intended to provide guidelines for handling adverse events 
but ultimate judgment will be the responsibility of the investigator.  In addition, as other situations are encountered and managed by the study team, this 
decision guideline chart will be updated and expanded so that it remains current and fully inclusive.