Clinical trial NCT02807623
Conditions: Immune System and Related Disorders
Sponsor: Womack Army Medical Center
Start date: 2016-09-01; Completion date: 2018-12-01
Enrollment: 300 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this clinical investigation is to evaluate the efficacy and immunologic effects of a non-pharmacological exercise intervention (push-ups) compared to an oral NSAID (ibuprofen) and an oral placebo to decrease local injection site inflammation symptoms of delayed pain, erythema, and edema and any impact on serologic antibody immune response after influenza vaccine receipt.

Detailed description:
The study will evaluate the efficacy and immunologic effects of a non-pharmacological exercise intervention (push-ups) compared to an oral NSAID (ibuprofen) and a blinded oral placebo to decrease local injection site inflammation symptoms of delayed pain, erythema, and edema and any impact on serologic antibody immune response after influenza vaccine receipt. A healthy military cohort will be randomly assigned to either perform push-ups consistent with their army physical fitness score, or to take a blinded oral medication which will be an NSAID (ibuprofen) or an oral placebo. The study will require three visits for assessment: on the day of vaccine receipt, 48-72 hours later and 21 -28 days later. The assessment visits will include injection site inspection, an injection site photograph, completion of symptom diaries and a validated pain scale and a laboratory blood specimen at the first and third visit to measure antibody level changes. The exercise participants will also be required to provide 1-2 fingerstick blood samples to evaluate for lactate, which is a byproduct of anaerobic exercise to measure if level of exercise effort achieved anaerobic metabolism. The study will evaluate if either of the interventions impacted perceived delayed pain, physical signs of inflammation or antibody response as measured by serology.

Arms: arm 1: Randomized and double blinded study participants assigned to Group A intervention will receive an oral NSAID of ibuprofen 800 mgs three times a day for 48 hours. arm 2: Randomized and double blinded study participants assigned to Group B intervention will receive an oral placebo three times a day for 48 hours starting immediately after influenza vaccine receipt. arm 3: Randomized study participants assigned to Group C will perform an exercise intervention of push-ups immediately after influenza vaccine receipt.
Interventions: intervention 1: Ibuprofen intervention 2: Compound Exercise of Push-ups intervention 3: oral placebo
Intervention descriptions: intervention 1: The participants will take their first dose of the study drug immediately after influenza vaccine receipt. The medication will be blinded and dispensed by a research pharmacist. The participants will receive instructions on the dosing, frequency and a recommendation to take with food or milk and will be provided a snack with their first dose. intervention 2: The participants will perform an exercise intervention of push-ups as immediately as possible but no more than 15 minutes after influenza vaccine receipt. The number of pushups performed will be at least 80% of the participants last Army Physical Fitness Test (APFT) score in one session. The number of pushups will be recorded. A baseline lactate fingerstick blood specimen will be collected with either the serology sample (if possible) or from the hand opposite the vaccine receipt arm prior to performing pushups and a second finger stick sample within 3-8 minutes, but no more than 15 minutes after vaccine receipt. intervention 3: The participants will take their first dose of the study drug immediately after influenza vaccine receipt. The medication will be blinded and dispensed by a research pharmacist. The participants will receive instructions on the dosing, frequency and a recommendation to take with food or milk and will be provided a snack with their first dose.

Protocol documents:
Prot_SAP_000.pdf: 
Document Cover Page 
 
Official Title of the Study: 
Do NSAIDS or Executing Exercise Decrease Local Erythema, Site Swelling & Pain After 
Inocculation: the NEED LESS PAIN Study 
NCT Number:  NCT02807623 
Date of Document: October 1, 2018 


EIRB Protocol Template (Version 1.10)
1.0
General Information
*Please enter the full title of your study:
Do NSAIDS or Executing Exercise Decrease Local Erythema, Site Swelling & Pain After 
Inocculation: the NEED LESS PAIN Study
 
 
*Please enter the Protocol Number you would like to use to reference the protocol:
Need Less Pain
* This field allows you to enter an abbreviated version of the Protocol Title to quickly identify 
this protocol.
 
 
Is this a multi-site study (i.e. Each site has their own Principal Investigator)?
No
 
 
Does this protocol involve the use of animals?
Yes
No
 
 
2.0
Add Site(s)
2.1 List sites associated with this study:
Primary 
Dept?
Department Name
Army - Womack Army Medical Center (WAMC)
 
3.0
Assign project personnel access to the project
3.1 *Please add a Principal Investigator for the study:
 
HOUSEL, LAURIE A
Select if applicable
Student
Site Chair
Resident
Fellow
 
3.2 If applicable, please select the Research Staff personnel:
 
A) Additional Investigators
Collins, Limone C 
 Co-Investigator
Mcclenathan, Bruce M, MD 


 Associate Investigator
Spooner, Christina Eve 
 Associate Investigator
B) Research Support Staff
BRUNADER, Janet ANN, BSN 
 Research Coordinator
Beltran, Thomas A 
 Team Member
Collins, Gervon Teressa 
 Team Member
Hussain, Mary 
 Team Member
Lamberth, Sherry L, PharmD, MSCR 
 Team Member
Lohsl, Connie Lynn, BSN 
 Research Coordinator
Nivens, Arline G, MS, PA ASCP, CRP, CMA 
 Research Coordinator
Ritschl, Jennifer Lynn, BSN 
 Team Member
Ryder, Stephanie L 
 Team Member
Turnquist, Jacob 
 Team Member
3.3 *Please add a Protocol Contact:
 
BRUNADER, Janet ANN, BSN 
HOUSEL, LAURIE A 
Hussain, Mary 
Lohsl, Connie Lynn, BSN 
Nivens, Arline G, MS, PA ASCP, CRP, CMA 
Spooner, Christina Eve 
The Protocol Contact(s) will receive all important system notifications along with the Principal 
Investigator. (i.e. The protocol contact(s) are typically either the Protocol Coordinator or the 
Principal Investigator themselves).
3.4 If applicable, please select the Designated Site Approval(s):
 
Add the name of the individual authorized to approve and sign off on this protocol from your Site 
(e.g. the Site Chair).
4.0
 
Project Information
4.1  Has another IRB/HRPP reviewed this study or will another IRB/HRPP be reviewing this study?
If Yes, answer the questions according to the IRB/HRPP Determination.
  Yes   
  No


IRB Name
Review Date
Determination
No records have been added
4.2  Is this a research study or a Compassionate Use/Emergency Use/HUD project?
 Yes   
 No
4.3  What type of research is this?
Biomedical Research
Clinical trial (FDA regulated)
Behavioral Research
Educational Research
Psychosocial Research
Oral History
Other
4.4  Are you conducting this project in pursuit of a personal degree?
  Yes   
  No
4.6  Is this human subjects research? (As defined by 32 CFR 219) 
 
Human subject means a living individual about whom an investigator (whether professional or 
student) conducting research: 
   (i) Obtains information or biospecimens through intervention or interaction with the individual, 
and uses, studies, or analyzes the information or biospecimens; or 
  (ii) Obtains, uses, studies, analyzes or generates identifiable private information or identifiable 
biospecimens.  
 Yes   
 No
4.7  Do you believe this human subjects research is exempt from IRB review?
  Yes   
  No
5.0
 
Personnel Details
5.1  List any Research Team members without EIRB access that are not previously entered in the 
protocol:
No records have been added
5.2  
Will you have a Research Monitor for this study?
Yes 
No 
N/A 


Research Monitor Qualifications
Ensure the individual has expertise consistent with the nature of risk(s) identified within your study and 
is independent of the team conducting the research.
Research Monitor Role:
Responsibilities:  The medical monitor will review the conduct of the protocol and ensure that the rights 
and health of all subjects enrolled in the study are adequately protected .
 
This will include:
 
1. Ensuring that the principal investigator notifies the monitor of new subject enrollments in the protocol 
on a routine basis.
2. Periodically reviewing documents to ensure that the approved protocol plan is being followed and 
informed consent has been obtained from all subjects.
3.  Reviewing all addenda, all annual progress reports, and all adverse event reports.
4.  Reviewing all unanticipated problems involving risk to the subjects or other serious adverse events 
and all subject deaths associated with the protocol and provide an unbiased written report of the event.
5. Reporting any concerns with the study promptly to the IRB.
If applicable, you may nominate an individual to serve as the Research Monitor:
No Users have been selected.
6.0
 
Data/Specimens
6.1  Does the study involve the use of existing data or specimens only (no interaction with human 
subjects)?
  Yes   
  No
7.0
 
Funding and Disclosures
7.1  Source of Funding:
Funding Source
Funding Type
Amount
: Other
DoD-Defense Health Agency-
Immunization Healthcare 
Brance
Internally funded
Total amount of funding:
607000
7.2  Do you or any other Investigator(s) have a disclosure of a personal interest or financial nature 
significant with sponsor(s), product(s), instrument(s) and/or company(ies) involved in this study?
  Yes   
  No
If Yes, complete and attach Conflict of Interest forms for all key personnel


8.0
 Study Locations
8.1  Is this a collaborative or multi-site study? (e.g., are there any other institutions involved?)
 Yes   
 No
8.2  Study Facilities and Locations:
Institution
Site Name
Site Role
FWA or DoD 
Assurance 
Number
Assurance 
Expiration 
Date
Is there an 
agreement?
IRB 
Reviewing 
for Site
Army
Womack 
Army 
Medical 
Center
Lead site
: WAMC 
IRB
DHA
WRNMMC
Performance 
site
: WAMC 
IRB
Other:
Other 
Institution 
Site
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FWA or DoD 
Assurance 
Number
FWA or DoD 
Expiration 
Date
Is there an 
agreement?
IRB 
Reviewing 
for Site
No records have been added
8.3  Are there international sites?
Attach international approval documents, if applicable, when prompted. Note: Ensure local research 
context has been considered
  Yes   
  No
8.4  Is this an OCONUS (Outside Continental United States) study?
  Yes   
  No
Select  the area of responsibility:
Have you obtained permission from that area of responsibility? (This is a requirement prior to study 
approval)
  Yes   
  No
9.0
 
Study Details
9.1  Key Words:
Provide up to 5 key words that identify the broad topic(s) of your study
Vaccine, vaccination, or immunization AND one of the following: Pain, intervention, time, exercise, 
NSAID, paracetamol, acetaminophen, naprosyn, ibuprofen, nonsteroidal anti-inflammatory, steroid, 
injection, side effect, adverse event, physical activity, pushup, muscle conditioning.


9.2  Background and Significance:
Include a literature review that describes in detail the rationale for conducting the study. Include 
descriptions of any preliminary studies and findings that led to the development of the protocol.  The 
background section should clearly support the choice of study variables and explain the basis for the 
research questions and/or study hypotheses.  This section establishes the relevance of the study and 
explains the applicability of its findings
The Brighton Collaboration (“Brighton”) is an independent, global nonprofit vaccine safety research 
network for health care professionals.  Brighton states, “attending to immunization pain supports 
immunization because it reduces suffering which improves the immunization experience, reduces 
subsequent non-compliance as a result of minimizing injection induced anxiety and pain and it also 
maintains the ethical principle of ‘do no harm.’” (Gidudu, Walco, et al. 2012).  Interventions to enhance 
vaccine comfort promote vaccine acceptability for all populations which may improve vaccine 
participation and thus herd immunity and/or population disease prevention.
 
Brighton has differentiated acute pain from the actual needle stick and vaccine injection which occurs 
upon vaccine receipt, from delayed pain which occurs within minutes to hours from inflammatory 
responses.  Delayed pain has three distinct categories defined as persistent pain, including at rest, pain 
with movement or touch and the impact of pain on functioning.  Per Brighton, these differing symptom 
groups may be independent or potentially related.  Existing literature evaluates interventions to mitigate 
immediate pain with injection, but only minimal research has been performed evaluating interventions to 
decrease local site pain and inflammation symptoms for delayed pain after vaccine receipt, and for most 
of this work, pain evaluation was a secondary endpoint and the populations were mostly infants and 
children. 
 
Influenza vaccine receipt is mandatory for military service members.  We reviewed the package inserts 
of US manufacturers of inactivated injectable influenza vaccine (IIV), and all identified injection site pain 
as the most common adverse reaction in pre-license studies (Afluria, 2015, Fluarix, 2014, Flublock, 
2014, Flucelvax, 2014, Flulavel, 2014, Fluvirin, 2014, Fluzone, 2014).  Local site pain has also been 
specifically identified as a vaccine safety concern by military populations (Porter, Bowens, Tribble, 
Putnam, Sanders & Riddle 2008).
 
In practice, non-steroidal anti-inflammatory medications (NSAIDS) are frequently recommended by 
providers to mitigate delayed post vaccination local and systemic vaccine adverse effects (Defense 
Health Agency, 2004).  There is some literature to evaluate the effectiveness of this practice, primarily 
with paracetamol, but little research has been performed in adult populations. Additionally, the impact on 
antigen immunogenicity not been adequately researched.  It is known that paracetamol impairs immune 
response in children post vaccine receipt and for this reason, it is not recommended to routinely treat 
children for systemic adverse effects (Prymula, et al. 2009). 
 
The Brighton Collaborative has published case definitions for immunization site pain both acute and 
delayed, and guidelines for collection, analyses, and presentation of immunization safety data (Gidudu, 
Walco et al. 2012). They have additionally provided the same resources for evaluation of swelling, 
induration and local site reaction.  Pain evaluation differentiates persistent pain, pain with movement or 
touch and impact on function, which is particularly pertinent to a service member whose daily 
requirements include demanding physical activity.  Within military lore, pushups are reputed to be an 
effective intervention to decrease post-vaccine local site discomfort.  There currently is literature to 
support enhanced antibody response to exercise and the use of exercise as a vaccine 
adjuvant.  However, little research has been performed to evaluate exercise as a nonpharmaceutical 
intervention for pain management. Multiple acute pain management interventions have been evaluated 
but little research has been performed for delayed pain.  There also has been little evaluation on the 
immunologic impact on antibody formation with of use of NSAIDS. Prophylactic use of oral analgesics are 
not endorsed for delayed pain management but it is commonly recommended in practice to patients who 
express concern or who report prior negative experiences (Gidudu, Walco et. al 2012). Clinical research 
to determine if antibody response in adults is affected by NSAIDS may elucidate best practice 
recommendations and as previously noted, interventions to address vaccine safety concerns could 
improve acceptability and participation thus leading to healthier populations.
 
Literature Review
The initial literature review search encompassed three topics of interventions for delayed pain from 
immunization, exercise as an adjunct for pain mitigation and serologic effects of NSAIDS, all which 
yielded sparse results. The search was widened to include any pain interventions, exercise effects on 
immunization and impact on immune response with NSAIDS or paracetamol. Only English language 
results were considered and article reference lists were also reviewed for pertinent articles.
 
Pain interventions


The interventions trialed to address pain can be categorized into three classes of interventions: 
pharmacologic, nonpharmacologic, or combined.  Nonpharmacologic included psychological techniques, 
physical techniques and devices. Acute immediate pain associated with the injection has been primarily 
the target of research with limited information found on interventions for  delayed pain. Multiple 
interventions have been trialed to address immediate pain during injection of vaccine, primarily with 
children and infants.  These include topical gels, sprays or creams (Abuelkeir et al. 2014, Berberich & 
Landman, 2009, Cohen & Hulubkov 1997, Dilli, Kucek, Izzet,  & Daller 2009,  Mawhorter, Daugherty, 
Ford, Hughes,  Metzger, & Easley, 2004; Taddio, Appleton et al. 2010; Taddio, Lord et al. 2010),  manual 
pressure, breast feeding (Dilli et al., Shah, Taddio & Reider 2009) oral sucrose solutions (Dilli et al., Shah 
et. al.) sucking swaddling, positioning, singing, psychological interventions of breathing, suggestion, child 
or parent directed distraction, bubble blowing, nurse directed distraction, parent coaching, cognitive 
behavioral interventions (Sparks 2001).  Distraction techniques including music (Krsitjansdottir, 2011), 
ipads,  relaxation and guided imagery (Kristjandottirn;  Nillson, Forsner, Finnstorm & Morelius, 2015) 
holding of infants, tactile techniques (Nikashima, Harada, Okayama & Kajii 2013, Taddio & Lord et al.,), 
and rattles and devices such a “shot blocker” or various devices (Berberich et al., Cobb & Cohen 2009). 
Taddio,  Ilserch et al. (2009)  published review of injection techniques to reduce pain. Shah et al., 
Taddio, Appleton et al., Taddio, Chambers et al. 2009, Taddio, Ilersich et al., Chambers, Taddio, Uman & 
McMurtry (2009) published extensive review articles and practice guidelines for acute pain. Most 
research interventions were targeted towards children or infants and few trials included the adult 
population (Maiden, Benton & Bourne 2003, Nikashima et al. and Taddio, Lord et al.). A fourth article by 
Russell, Nicholson & Naidu (2014) assessed a pharmacologic and a nonpharmacologic intervention 
however this was for a nonvaccine intramuscular injection. Research articles with interventions for acute 
pain only for infant population only were  not further reviewed.
 
Pharmacologic interventions consisting of topical gels, creams and sprays and were generally found to be 
effective compared to placebo (Abuelkeir et al. 2014, Dilli et al. 2009) or superior to self-distraction 
(Taddio & Lord et al. 2010).  Nonpharmacologic interventions included application of manual pressure 
(Nikashima et. al, 2013), prewarming of vaccine (Maiden et al.  2003), freezing needles (Hogan, Kikuta 
& Taddio, 2010), and devices such as shotblocker (Cobb & Cohen 2009), all which were 
ineffective.  Psychological techniques such as distraction demonstrated benefit (Krsitjansdottir, 2011) 
although less than other techniques (Taddio and Lord, 2010).
 
Russell, Nicholson & Naidu’s  (2014) research demonstrated benefit of an intramuscular lidocaine 
(lignocaine) and “Mr. Buzzy”  however this was with IM benzathine PCN receipt and was not randomized. 
Mr. Buzzy is a device which applies cold and vibration and is marketed for immunization pain, however 
the research data located for this device was related to venipuncture or for nonimmunization 
intramuscular injections, and none was found with key word searches or on the list cited on their own 
marketing product web site.
 
 
Exercise effects
Data on exercise as an adjunct to serological response to immunization is present. The results appear to 
vary based on the vaccine, age of the cohort, and the type of exercise tested.
Vaccines studied included influenza, pneumococcal, meningococcal, varicella, Tetanus/diphtheria. 
Serological response to individual influenza vaccine strains varied within individual study Groups.
 
Elders, who have the most immunesenescence, were most likely to demonstrate enhanced antibody 
response to exercise interventions. In some studies with half dose vaccine given to younger participants, 
serologic response to exercise was more prominent.  Younger healthy individuals receiving full doses of 
vaccine were less likely to demonstrate benefit from exercise interventions. Younger healthy individuals 
receiving half dose vaccine did demonstrate benefit.  One study also demonstrated benefit to 
psychological stress. Gender differences in response were also noted in differing studies, but no single 
trend was consistent.
 
Types of exercises trialed included eccentric exercises such as arm curls and lateral raises, use of 
resistance bands, and aerobic forms with ergometers, walking programs, elite swimmers, 
triathletes,  flexibility regimens and Tai Chi. Other variants included exercise intensity and timing, such 
as immediately preceding vaccine receipt vs. an overall program of fitness without specific temporal 
correlation to receipt.
 
Site pain was evaluated in some of the studies involving eccentric exercises. Of interest, in the study by 
Campbell, Edwards, Ring, Drayson Bosch, Inskip et al.  (2010), the exercise group reported increased 
immediate and delayed pain at 48 hours compared to control group. In another study using similar 
exercise treatments, the exercise group reported more pain at every time interval of immediate, 6 hour 
and 24 hours than the control group (Edwards, Burns, Allen, McPhee, Bosch, Carroll et al., 2007). 
Another exercise intervention group who used arm bands for exercise and received pneumococcal 
vaccine also reported more pain compared to controls. (Edwards, Pung, Tomfohr, Ziegler, Campbell, 
Drayson, et al. 2012).  
 


In another trial, young healthy adults performed three arm exercise movements with resistance bands or 
performed no exercise and then received either half dose or full dose of pneumococcal vaccine. The 
exercise groups demonstrated superior antibody levels compared to the either the half or full dose 
resting groups. (Edwards, Pung, et al. 2012).
 
Edwards, Kate M, Campbell, John P., Ring, Drayson, Bosch, & Downes et al.  (2010) also evaluated 
exercise intensity as an adjuvant to half dose influenza vaccine. The participants were assigned to a 
60%, 80% or 110% of their predetermined capacity to perform lateral arm raises and biceps curls.  The 
antibody response to the half dose vaccine was demonstrated in some but not all groups, and the 
antibody response did not vary with exercise intensity.
 
Campbell et al. (2010) evaluated effects of vaccine timing on the efficacy of  eccentric exercise with the 
lateral raises arm biceps curls in a young adult cohort who then received influenza vaccine. In this study, 
no serological benefit was noted and it was attributed to the age of the cohort.
 
Edwards, Burns, Reynolds, Tracy, Carroll, Drayson, & Ring (2006) also evaluated exercise via ergometer, 
vs. a psychological stress intervention of a series of complex arithmetic tasks in a competitive contest 
with rewards and aversions prior to IIV receipt. Compared to the control group, both the exercise stress 
group and the psychological stress group demonstrated enhanced immune response compared to the 
control group.
 
Edwards Burns Adkins, Carroll, Drayson & Ring (2008) evaluated the antibody response to 
meningococcal vaccine in young adult subjects who were exposed to either exercise or mental stress. 
Men but not women demonstrated enhanced effect to both interventions.
 
Kohut, Arntson, Wanglok, Rozebloom, Yoon, &  McElhaney (2004) demonstrated moderate exercise 3 
times a week for 10 months by a cohort over age 65 improved antibody titer response to influenza 
vaccine compared to age matched controls. Additionally antibody titers were comparable to young 
subjects for one serotype in this small study.
 
Shuler, Lloyd, Clapp, Abadie, & Collins (1999) studied found no differences in antibody response to two 
strains of influenza virus vaccine in college students categorized by fitness level.
 
In another trial healthy elders were randomized to perform Tai Chi for 25 weeks or receive health 
education. Prior to receipt of Varivax vaccine, the Tai Chi Group demonstrated levels of cell mediated 
immunity (CMI) comparable to levels induced by vaccine in the health education Group. After vaccine 
receipt, their varicella zoster specific CMI was comparable to levels previously observed in adults 30 
years younger (Irwin, Olmstead, & Oxman, 2007).
 
Shuler, Leblanc, & Marzilli (2003) identified enhanced antibody response to influenza vaccine in elders 
who exercised based on a self-reported activity scale. Antigen formation was significantly greater for one 
component of the vaccine.
 
Randive, Cook, Kappus, Yan, Lane, Woods et al. (2013) evaluated an acute aerobic exercise intervention 
in an older adult population and its effect on influenza vaccine titers. A benefit was seen only in women 
and only to the H1N1 strain of the trivalent vaccine.
 
One study introducing a 16 week walking program as a lifestyle intervention to sedentary women who 
then received pneumococcal vaccine did not demonstrate benefit to antibody response (Long, Ring, 
Bosch, Eves, Drayson, Calver et al. (2013).
 
Long, Ring, Drayson, Bosch, Campbell, & Bhabra et al. (2012) evaluated brisk walking in a young cohort 
and an over age 60 cohort prior to receipt of pneumonia vaccine or influenza vaccine. Neither cohort 
demonstrated increased antibody response to either vaccine.
 
Kohut, Nickolaus, Russell & Cunnick (2002) evaluated lifestyle including exercise in elders. Serology for 
IgG and IgM were greater in the vigorous exercise group.
 
Woods, Keylock, Lowder, Viera, Zelkovich, Dumich et al. (2009) evaluated effects of aerobic exercise and 
a flexibility exercise group in a previously sedentary elderly population. The exercise intervention was 
started 4 months prior to vaccine receipt and continued for 6 months after and resulted in enhanced 
sustained antibody levels in the aerobic group. The vaccine receipt timing was correlated with exercise 
session.
 
Gleeson, Pyne, McDonald, Clancy, Cripps, Horn et al. (1996) evaluated antibody response to 
pneumococcal vaccine in elite swimmers in an intense training period. They found no decrease in 
immune response compared to age and sex-matched peers.
 


Whitman, &  Blannin (2003) evaluated differences of heavy training vs. light training on a cycle 
ergometer to influenza vaccine resulted in no effect on the kinetics of the IgG response. The vaccine 
receipt timing was correlated with exercise session.
 
Bruunsgaard, Hartkopp, Mohr, Konradsen,  Heron, Mordhorst, & Pederson, (1997) found no difference in 
antibody titers in men after Td and pneumococcal vaccine receipt  immediately after completion of a one-
half iron man compared to controls.
 
Keylock,  Lowder,  Leifheit, Cook, Mariani,  Ross et al. (2007) found higher antibody, but not cell –
mediated, responses to vaccination in high physically fit elderly to two of three strains of fluzone and Th2 
response to tetanus toxoid.
 
Systemic pharmacologic interventions for delayed pain reduction
 
NSAIDS or acetaminophen class medications are routinely recommended to reduce local and systemic 
adverse effects of immunization (Defense Health Agency, 2004).  Pharmacologic interventions have been 
evaluated for reduction of delayed adverse events including fever, fussiness, and local site reactions, but 
there is a paucity of data on serological response, adult populations and  use of NSAIDS.
 
 Ibuprofen was evaluated in infants who demonstrated decreased unusual crying in addition to decreased 
local reactions and some systemic reactions, but not fever in infants who received DTaP (Diez-Domingo, 
Planelles, Baldo, Ballester, Nunez, Jubert et al. 1998). 
 
Jackson, Dunstan, Starkovich, Dunn, Yu, Nelson, et al. (2006) compared prophylactic treatment with 
acetaminophen or ibuprofen for local reaction adverse effect mitigation from the fifth dose of DTaP in 
children. The investigators found no benefit to either medication regimen. Pain and fever were secondary 
endpoints and also did not demonstrate benefit.
 
Hayat, H. Humera, Khan, Parwez, & Hayat, G.  (2011) evaluated paracetamol in infants who received 
DTP which demonstrated decreased fever and fussiness but no impact on site reactions.
 
Rose, Jeurgens, Schmoele-Thoma, Gruber, Baker & Zielen (2013)  demonstrated paracetamol starting at 
vaccine receipt decreased fever in infants but not toddlers who received HBV-IPV/Hib, PCV-7 & DTaP. 
The paracetamol also tended to prevent site reactions but the authors felt it was not significant 
compared to the controls. Yalcin et al. demonstrated a single prophylactic dose of acetaminophen had no 
benefit on systemic reactions, or local site reactions of swelling, pain or erythema. 
 
Doedee, Boland, Pennings, de Klerk, Berbers, van der Klis et al. 2014 evaluated the serological effects of 
paracetamol in adults on hepatitis B vaccine receipt. paracetamol was given starting either at the time of 
vaccine receipt (prophylactic) or six hours later (therapeutic). A control group received none. The 
prophylactic group demonstrated a 26% reduction in antibodies compared to the control group. The 
therapeutic group was not different from the control group. All groups achieved protective levels.
 
Prymula, Siegrist, Chlibek, Zemlikova, Vacknova, Smetana et al. 2009, studied the effect of prophylactic 
paracetamol in infants receiving pneumococcal/H. flu protein D conjugate (PHiD-CV), and a diphtheria, 
acellular pertussis, hep B, inactivated polio virus, and H. flu type B (DTPa/-HBV-IPV-/Hib). The 
paracetamol group did demonstrated reduced frequency of significant fever, but this event was overall 
rare. The paracetamol group also demonstrated lower antibody responses compared to controls, which 
persisted after boosting for several of the vaccines.
 
Das, Panigrah & Naik (2014) performed a systematic literature review and  stated they felt there is a 
favorable benefit to prophylactic antipyretic administration for both local and systemic symptoms. They 
cited lack of sufficient RCT data or based on Prymula solitary research and cited four points related 
to  clinical and epidemiologic data and known immunological processes.
 
 
REFERENCES:
 
Abbott K, & Fowler-Kerry, S. (1995). The use of a topical refrigerant anesthetic to reduce injection pain 
in children. 
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(8), 584-590.
Journal of Pain and Symptom Management 10
 
Abuelkheir, M., Alsourani, D., Al-Eyadhy, A., Temsah, M., Meo, S., & Alzamil, F. (2014). EMLA(R) cream: 
A pain-relieving strategy for childhood vaccination. 
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(2), 329-
Journal of International Medical Research 42
336.
 
Afluria US Package Insert for 2015-2016. 2015. bioCSL version 44. Retrieved from http://www.fda.gov
/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM263239.pdf
 
Berberich, F., & Landman, Z. (2009). Reducing Immunization Discomfort in 4- to 6-Year-Old Children: A 
Randomized Clinical Trial. 
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Bruunsgaard, H., Hartkopp A., Mohr, T., Konradsen, H., Heron, I, Mordhorst, CH, & Pederson, B.K. 
(1997). In vivo cell-mediated immunity and vaccination response following prolonged, intense exercise  . M
 29(9), 1176-1181. [abstract].
edicine & Science in Sports & Exercise
 
Campbell, John, P., Edwards, Kate M., Ring, Christopher, Drayson, Mark T., Bosch, Jos A., Inskip, 
Andrew, et al. (2010). The effects of vaccine timing on the efficacy of an acute eccentric exercise 
intervention on the immune response to an influenza vaccine in young adults. Brain, Behavior and 
 (24) 236-242.
Immunity
 
Chambers, C., Taddio, A., Uman, L., & McMurtry, C. (2009). Psychological interventions for reducing pain 
and distress during routine childhood immunizations: A systematic review. 
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S103.
 
Cobb, Jean, E., & Cohen, Lindsey, L. (2009). A randomized controlled trial of the Shotblocker for children’
s immunization distress  
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. The Clinical journal of Pain
 
Cohen Reis, E., & Holubkov, R. (1997). Vapocoolant Spray Is Equally Effective as EMLA Cream in 
Reducing Immunization Pain in School-aged Children. 
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9.3  
Objectives/Specific Aims/Research Questions:
Describe the purpose and objective(s) of the study, specific aims, and/or research questions/hypotheses
The purpose of this clinical investigation is to evaluate the efficacy and immunological effects of 
interventions to decrease local injection site inflammation symptoms of erythema, edema and pain after 
vaccine receipt. 
Interventions to mitigate acute pain associated with vaccine have been studied but little research has 
been performed to quantitatively evaluate interventions for mitigation of local site effects and delayed 
pain associated with vaccine receipt. The clinical investigation would address gaps in the literature 
concerning both management and serological effects of the interventions.
 
 HYPOTHESES/RESEARCH QUESTIONS:
At each time point, mean pain scores as indexed by the BPI will be equivalent across groups.
At each time point, mean objective signs of inflammation will be equivalent across groups.
At each time point, mean serologic response to immunization will be equivalent across groups.
 
 
SPECIFIC AIMS/SIGNIFICANCE:  
Interventions to mitigate acute pain associated with vaccine have been studied but little research has 
been performed to evaluate interventions for mitigation of local site inflammation effects and delayed 
pain associated with vaccine receipt in adults. Delayed site pain has been specifically identified as a 
vaccine safety concern by military populations (Porter et al., 2008) and use of the pushup type 
compound exercise to decrease delayed pain is reputed to be part of military folklore. 
 
Addressing concerns of safety and comfort promotes acceptance of both required and optional vaccines. 
This could increase vaccine rates achieving public health immunization and disease prevention goals. 
Previous clinical studies support exercise enhances antibody response in some populations. Little 
research has been performed on the serologic impact of systemic pharmaceuticals after immunization 
receipt. Paracetamol has been demonstrated to decrease immune response in children but little research 
has been performed on the serological impact in adult populations. Additionally the serological impact of 
NSAIDS, a medication class with much greater anti-inflammatory effects than paracetamol, has had little 
evaluation. Serologic data could provide guidance for best practices.
 
9.4  Study Design:
Describe study design in one to two sentences (e.g., prospective, use of existing records/data
/specimens, observational, cross-sectional, interventional, randomized, placebo-controlled, cohort, etc.). 
Specify the phase – Phase I, II, III, or IV – for FDA-regulated investigational drug research
This study utilizes a prospective randomized control trial design.  Participants will be randomized to one 
of three treatment arms and both study personnel and study participants will be blind as to the type of 
medication received (NSAID or placebo).  Participants will be assessed during 3 visits, over a 3 to 4 week 
period.
9.5  Target Population:
Describe the population to whom the study findings will be generalized
Male and female active duty service members who will be receiving influenza vaccine as required per 
DoD policy.


9.6  Benefit to the DoD:
State how this study will impact or be of benefit to the Department of Defense
MILITARY RELEVANCE:  Address gaps in current literature related to:
1. Interventions to decrease signs of inflammation, which could impair activity performance 
2. Interventions to decrease delayed pain concerns of soldiers which have potential to
             a. increase vaccine acceptability
b. decrease vaccine anxiety
c. decrease vaccine hesitancy for optional vaccines for other populations for whom other 
vaccine is optional such as dependents . For example HPV is recommended for all males and 
females through age 26, and it is an optional vaccine for military service members. This vaccine 
is a very effective anticancer vaccine, but currently full series completion rates remain low.
 
Reference: http://www.cdc.gov/vaccines/who/teens/vaccination-coverage.html
10.0
 
Study Procedures, Data Management, and Privacy
10.1  Study Procedures:
Describe step-by-step how the study will be conducted from beginning to end
Study briefing and consents to be performed by IHB staff prior to study enrollment as follows:
 
1. Recruitment
 
WRNMMC site: Recruitment posters will be placed at influenza drive sites and on the WRNMMC Intranet.
 
WAMC site: The principal investigator, associate investigators, study nurse, and DHA-IHB research staff 
will recruit and enroll subjects, presenting the study content to potential participants. Investigators at 
WAMC will retain original signed consents. Participants will be counseled that a decision not to enroll will 
not affect their standard of care and is independent of their decision to receive the influenza vaccine.
Recruitment Process Details:
Recruitment posters (see attachment A) will be placed at influenza drive sites. At Fort Bragg this will be 
the 82nd SRC. The research staff will contact the NCOIC at the 82nd SRC to identify scheduled dates of 
influenza vaccinations. The research staff will be present at the 82nd SRC during scheduled dates of 
influenza vaccinations.  The research staff will provide a briefing at the 82nd SRC just prior to or during 
influenza vaccination drive. The briefing will notify individuals who will be receiving influenza vaccine per 
their military requirements of the opportunity to participate in the voluntary study. The research staff will 
meet with soldiers at the SRC and query if any senior enlisted (E5-E9) or officers (O1-O-10) are present. 
The potential subjects will be briefed in 3 separate groups consisting of lower enlisted (E1-E4), senior 
enlisted (E5-E9) and officers (O1-O-10) to eliminate potential for coercion, and the groups not being 
currently briefed will be requested to leave the immediate area for the duration of the brief. The research 
staff will sequentially rotate the order of groups briefed to decrease the potential for inadvertent 
introduction of age or socioeconomic bias as there will be a limited number of participants accepted each 
day. The research staff will then read the briefing script (see attachment: k). 
 
The briefing will describe the following study details:
 
The study description stating that we will assess pain at the injection site after flu vaccination to 
develop methods of decreasing vaccination pain.
Participants receiving an influenza vaccine today may qualify.
 
Participation includes: 
One (1) initial visit prior to receiving your flu shot and two (2) follow-up visits.
Vaccination site pain and appearance assessments.
Random assignment to Ibuprofen, placebo or exercise intervention.
One venous blood draw for visit #1 and #3 (two total) and #1 or #2 POC finger sticks for the 
exercise intervention group (first POC will attempted to be collected from the venous specimen 
blood draw).
Abstinence from pain relief medications and alcohol for 2-3 days after receipt of vaccine, until the 
second visit is completed.


Participants who complete the study will receive financial compensation for the lab draws.
 
Screening & Consent: WAMC & WRNMMC
Prior to recruitment, as part of Standard of Care, the individuals who volunteer to be considered for this 
clinical study will likely have completed the WAMC Adult Influenza Screening form which will be reviewed 
per standard organizational procedures to determine if the subject is appropriate to receive IIV.  This 
form will not be collected or reviewed by the research staff until after the subject is consented. 
Individuals who are scheduled for influenza vaccine receipt and are interested in the study will meet with 
the research staff at the IHB research office adjacent to the SRC prior to receipt of vaccine to obtain 
informed consent.  The research staff will provide a description of the study requirements including three 
assessment visits, receipt of one of three interventions of oral medication, oral placebo, or performance 
of pushups at a minimum of 80% of their last APFT in one session, completion of 2 symptom diaries, and 
collection of two blood specimens for serology and 1-2 POC finger stick specimens for the exercise 
intervention group. Persons wishing to be considered for participation will be screened for eligibility by 
the research staff by completion of the Study Eligibility Screening Form (see attachment #B). The 
Eligibility Screening Form does not contain identifying information.  All sections of the form will be 
completed prior to consent with the exception of the question regarding pregnancy testing.  Females of 
childbearing age will be required to complete a pregnancy test after being consented.  After the subject 
is consented, the previously completed Adult Influenza Screening forms will be reviewed by the research 
staff to ensure congruence with the Study Eligibility Screening Form and confirm no contraindication to 
vaccination exists. In the event no influenza screening form was completed at the SRC, the research staff 
will complete such screening form after informed consent is obtained.  Also following consent, 
the research staff will review the candidates’ current medication list for medication classes as cited in the 
exclusion criteria and counsel the candidates on any medications they will need to abstain from for the 
first 2-3 days of the study, until Visit 2 is completed.  Prescription pain medications ordered on a routine 
basis will be considered necessary and the medication benefits to the patient will supersede study 
participation, thus making the candidate ineligible. Prescription pain medications ordered on an as 
needed basis are acceptable if the participant states they anticipate they would not be requiring the 
medication or accept abstinence from the medication for the first 2-3 days of the study, until Visit 2 is 
completed. Any question by the study staff concerning the appropriateness of a current subject 
medication will be discussed with the principal investigator and /or associate investigator to determine if 
patient can continue in the study.
 
The research staff will also advise the candidate that all over- the-counter medications need to be 
avoided or reviewed and approved by research staff for anti-inflammatory or pain relieving properties 
prior to use. The research staff will contact the PI or AI for any questions or clarification as needed. Any 
new prescription medications started after the start of the study will be considered necessary and the 
benefits to the patient will supersede the study. Enrolled subjects identified as having exclusion criteria 
after reviewing the screening forms will be counseled they are ineligible for continuation in the trial and 
referred to back to SRC providers to follow their usual protocols for influenza vaccine receipt.
 
Subjects will receive counseling from the research staff to meet the established guidelines for informed 
consent:  to include a statement of the purpose, randomization process, use of placebo control, use of 
prescription dose ibuprofen, foreseeable risks, potential benefits, research staff contact information, 
rights and responsibilities, and that participation is voluntary. After consent, subjects will be asked for 
contact information and consent to contact by telephone or email for clarification of medical history, and
/or prior immunizations and/or adverse events and to remind subjects of follow-up visits.  During the 
consent process the research staff will also provide counseling and the participant will complete the 
HIPAA form. The data and specimens collected may be of significant utility for future studies. Subjects 
will be asked for consent for future study to include use of collected specimens and use of data 
collected.  Subjects will be asked for permission to be contacted for future studies and the participant will 
have the option to consent or refuse permissions for future studies without effect on participation in this 
proposed study. Subjects interested in study participation will complete the study consent/HIPAA form 
(see attachment C.) with required initials, signature, and date.
 
3. Randomization and Treatment Arms: WAMC & WRNMMC
Once fully enrolled, the participants will then be randomized to treatment arms Group A, Group 
B or Group C.  A random number sequence will be generated via SPSS. The first third  of the 
random number sequence will be assigned to Group A, the second third to Group B and the 
remaining third to Group C. The sequence will then be reordered in ascending order (i.e. 1 = 
Group C, 2 = Group A, 3 = Group A, 4 = Group B… ). As individuals are recruited and consented 
they will be given the next number in the sequence and thus are randomly assigned. Should 
dropouts occur, replacement participants will be assigned to the same group as the participant 
whom they are replacing.  The replacement participant’s Study ID number will be the next 
available after the required 216.  For example, if participant 35 drops out prior to completion 
and the individual was assigned to group C, then a replacement will be recruited and assigned 
the study ID number 217 and group C.  
 


Complete data set will be defined as completion of the three evaluations, all laboratory specimen 
collection, reported receipt of a minimum of four doses of study drug for Groups A&B, and the 
exercise intervention at 80% or above APFT for Group C in a single session or a lactate 
measurement of 15mmol/L or greater 3-15 minutes post exercise should the 80% threshold not 
be achieved.
 
Group A and Group B will receive either ibuprofen 800 milligrams orally three times a day for 48 
hours (6 doses ) or a placebo starting immediately after vaccine receipt and the initial dose will 
be  observed by the research staff (the participants will self-dose subsequent doses and record 
in a diary time of receipt). Group C will perform the exercise intervention.
 
The research staff will provide the study drug to the participants enrolled in the pharmacologic treatment 
arms Group A and Group B. The medication will be blinded into Group A or Group B and dispensed by the 
research pharmacist. Only the research pharmacist will know which is ibuprofen and which is 
placebo.  The research staff will provide instruction on the oral medication dosing, frequency and a 
recommendation to take with food or milk. The participant will be provided with a snack such as crackers 
for receipt of the first dose of study drug. The Group C will also be provided the same snack opportunity. 
The participants will be given the Visit 1 Vaccination Diary Card (attachment D) measurement tools, how 
to measure and the documentation requirements will be explained by the r. The participants will also be 
instructed not to take any topical or oral over the counter medications for 2-3 days of the study, until 
Visit 2 is completed unless they verify the medication does not contain a pain relieving and anti-
inflammatory medication with  a pharmacist and/ the study staff. This includes counterirritants such as 
menthol, methylsalicylate, camphor menthols, capsiacins, acetaminophen, opioids, tramadol, NSAID or 
salicylate containing products.
 
Initial Evaluation: Visit 1 (time 0)
The research staff will complete the Visit 1 Site Evaluation and Vaccination Capture Form (attachment E), 
Demographic and Military History Survey (attachment F),  a Brief Pain Inventory (attachment G), and 
visit 1 Health Status Questionnaire (attachment H). The subjects will be provided computer use to access 
their previous APFT score which will be visually confirmed by the research staff.  The data collected will 
be consistent with the Brighton standards for immunization research for subjective pain assessment and 
objective site assessment for local reaction swelling and induration. Subjects will identify their non-
dominant arm for assessment and vaccine receipt. In the event the assessment reveals the non-
dominant arm is unsuitable for vaccine receipt (new tattoo, abrasion, etc.) then the opposite arm will be 
assessed and used for vaccination. If the subject states they are ambidextrous and do not have an 
identifiable arm dominance, the left arm will be used.  The research staff will perform assessments of the 
patient arm to include site inspection, arm circumference measurement at mid deltoid of the upper arm 
to receive vaccine, and a site photograph. An identifying label with the subject number will be included in 
the site photograph. To facilitate data reliability, arm assessment and measurement will be performed by 
the same research staff for a given participant when possible at the follow-up visits #2 & #3. Laboratory 
specimen of 10 milliliters for baseline serology will be collected by the research staff or lab personnel and 
baseline POC testing for lactate for the exercise Group will be performed. Residual blood from the serum 
collection will be used for the POC lactate if possible, however a fingerstick specimen may be required if 
this is not successful. The participants will be given the current Influenza Vaccine Information Statement 
per CDC and provided opportunity for review and to ask any questions.
 
 
After completion of these assessments the participants will receive their inactivated injectable influenza 
vaccine using standard of care technique (see below). For consistency in technique, when possible, all 
participants will receive their vaccine injection by the same nurse. The research staff will complete 
vaccine documentation sections of the Adult Influenza Screening Form. The research staff will provide 
the subject with a completed documentation card for proof of vaccine receipt. All participants will 
complete a modified Brief Pain Inventory (BPI)  for data collection of acute pain during the vaccine 
receipt. The participants assigned to Group A and Group B will take their study medication immediately 
after vaccine receipt and this will be observed by the research staff.  Study medication will be labeled 
with subject identification number (SID) and contain 6 doses for 48 hours of medication.  The last 5 
doses will be taken home for self-administration approximately every 8 hours.   The research staff will 
direct and assist these participants in logging the first dose in the Visit 1 Vaccination Diary Card.
 
The participants assigned to Group C (exercise) will perform pushups as immediately as possible, but 
within 15 minutes of IIV receipt and observed by the research staff. The goal will be 80% or above of the 
subjects reported last APFT score in one session. The number of pushups will be recorded. A finger stick 
lactate will be collected from the hand opposite to the vaccination arm. within 3-8 minutes, but no more 
than 15 minutes, of completion of the pushups.
 
The research staff will notify the research pharmacist of the names and Social Security numbers of 
participants within 24 hours of enrollment, so the pharmacist may enter into the participant’s medical 
record prescription list they are taking a study medication.
 
Second Evaluation: Visit 2 (time 48-72 hours)


The subjects will return to the IHB research office within the time frame of 48-72 hours of vaccine 
receipt. The staff will collect the Visit 1 Vaccination Diary Card and receive receipt of any returned study 
medication, which they will document the number of missed doses.  The subject will complete the Brief 
Pain Inventory and the staff will complete the Visit 2 Health Status Questionnaire (attachment I). 
The research staff will perform objective site assessment to include measurement of arm circumference, 
injection site inspection and measurement any erythema or induration and a site photograph.  An 
identifier with the subject number will be included in the site photograph. For interrater reliability, when 
possible, the assessment will be performed by the same research staff member who performed the initial 
assessment.
 
The subject will receive compensation in the amount of $50 per blood draw ($100 total); payments will 
be made via direct deposit to the subject's banking account or via a $50 gift card. No compensation will 
be provided for visit #2 which does not include any type of blood sampling.
In the event of significant immunization adverse reaction the patient will be referred by the research 
staff to follow-up with DHA-IHB as needed. Also the patient may self-refer to DHA-IHB by calling the Fort 
Bragg office 910-432-4015 or the 24/7 DOD call center number 1-877-438-8222. The 24/7 DOD call 
center card will be provided to each patient as a contact number for vaccine specific concerns.
 
 
Third Evaluation: Visit 3  (time 21-28 days)
The subjects will return to the IHB research office within the time frame of 21-28 days of vaccine receipt. 
The research staff will collect the symptom diary, and the subject will complete The Visit 3 Health Status 
Questionnaire (attachment J) and a BPI.  The research staff will perform objective site assessment to 
include measurement of arm circumference,  injection site inspection and measurement any erythema or 
induration and a site photograph. An identifier with the subject number will be included in the site 
photograph.   For inter-rater reliability, as possible, the assessment will be performed by the same 
research staff member who performed the previous assessments. Serology #2 following the same 
procedure as visit #1 will be collected. The subject will receive compensation for visit #3. A debriefing by 
staff will be completed.
 
Study Medications:
The study medications will be obtained from a national compounding pharmacy for consistency in 
appearance and to enhance blinding and the medications will be shipped to the research staff. The 800 
milligram ibuprofen dose will be dispensed in units of 400 milligrams each. The research staff will then 
transport the study drugs to Womack research pharmacist who will repackage them and dispense as 
medication Group A or medication Group B. Only the research pharmacist will be aware of which 
medication is ibuprofen and which is placebo. The research staff will pick up the study medications from 
the pharmacist prior to enrollment and will repeat this process as needed to have adequate supplies 
available.  Medication will be batched if needed to ensure potency within manufacturer expiration dates. 
Medication and placebo containers shall be counted and logged in a spreadsheet upon receipt from the 
pharmacy. Medication and placebo will remain in the original, pharmacy labeled, tamper resistant 
container and stored at the research office in a locked cabinet away from moisture, at room temperature 
(20- 25°C or 66-77°F) until administered by the research nurse. The investigational pharmacy will 
perform site visits to monitor inventory, storage conditions and documentation. Study medications not 
used or returned by subjects to the research staff will be returned to pharmacy for destruction. The 
pharmacist will notate and certify the receipt and destruction of any expired, unused or returned study 
medications.  At the end of the study, the pharmacist will unblind the study and certify the identification 
of treatment A and B.
 
Per Micromedex, all of the NSAIDs possess anti-inflammatory, antipyretic, and analgesic properties with 
overall therapeutic equivalence. Ibuprofen was selected due to its ubiquitous use both prescription and 
over- the- counter in lower doses such that allergy or intolerance would likely already be known. 
Although the FDA no longer uses pregnancy categories, ibuprofen was last categorized as Pregnancy 
Category C in first and second trimester in pregnancy and D during the third trimester. Ibuprofen is used 
for fever and pain control and for the treatment of several rheumatologic conditions. The mechanism of 
action most likely produces anti-inflammatory, antipyretic, and analgesic effects by inhibiting the 
cyclooxygenase enzyme, leading to decreased prostaglandin production and decreased pain and 
inflammation. The dosing ranges vary by indication from 1200-3200 milligrams/day. The dosing was 
selected due to the anti-inflammatory effects are more prominent in higher doses enhancing this clinical 
trials’ potential to measure endpoints.  The adverse effect potential is minimal due to the short duration 
of therapy and the safety profile of the medication. The most common adverse effect in an open-label 
study given to a population with rheumatoid arthritis was epigastric pain in 15% of participants.  Those 
subjects received 3000 mg/day for four weeks duration. A recent FDA advisory raised concerns for 
increased cardiovascular risks for heart attack and stroke with use of NSAIDs. We consider this risk in 
the study population to be minimal because compared to general populations this population is overall a 
young, fit, non-obese cohort who receive consistent recommended preventive care such as lipid 
screening and management. Additionally, the treatment regimen is only a two day course.  The FDA 
warning states cardiovascular events can occur early in a treatment regimen, the cited course is still in 
“weeks” not days.  Due to the concerns of this risk we will exclude any applicant with a history of 
cardiovascular disease. In the unlikely event of a clinical emergency requiring the clarification if the 


subject received NSAIDs or placebos, the PI or AI can be contacted and discuss if unblinding is necessary 
and can work with the research pharmacist for unblinding.
 
The influenza vaccine is not a study medication and participant receipt is per their active duty 
requirements.  During the influenza season, the FDA licensed trivalent or quadrivalent injectable 
influenza vaccine will be used for all study participants at the Fort Bragg site. The same trivalent or 
quadrivalent vaccine chosen for a given flu season will be administered throughout the season to 
maintain consistency of vaccine product for study subjects.
 
Multisite: WRNMMC-Recruitment, Screening and Consent summary
 
Recruitment posters will be placed at influenza drive sites and on the WRNMMC Intranet. Active duty 
males and females age 18 and older.
 
Prior to recruitment the individuals who volunteer to be considered for this clinical study will have 
completed the WRNMMC Adult Influenza Screening form which will be reviewed per standard 
organizational procedures to determine the subject is appropriate to receive IIV. Individuals who are 
scheduled for influenza vaccine receipt will meet with the research staff at the IHB research office prior 
to receipt of vaccine for eligibility screening and counseling to obtain informed consent. The IHB Study 
Nurses will provide a description of the study requirements including three assessments visits, receipt of 
one of three interventions of oral medication, oral placebo, performance of pushups at a minimum of 
80% of their last APFT in one session, completion of 2 symptom diaries, and collection of two blood 
specimens for serology and 1-2 POC finger stick specimens for the exercise intervention group. Persons 
wishing to be considered for participation will be screened for eligibility by the IHB Study Nurses by 
completion of the Study Eligibility Screening Form (see attachment #B). Females of childbearing age will 
be required to complete a pregnancy test. The previously completed Adult Influenza Screening forms 
which will be reviewed by the IHB Study Nurses to ensure congruence with the Study Eligibility Screening 
Form and confirm no contraindication to vaccination exists. The IHB Study Nurses will review the 
candidates’ current medication list for medication classes as cited in the exclusion criteria and counsel 
the candidates on any medications they will need to abstain from for the first 2-3 days of the study, until 
Visit 2 is completed. Prescription pain medications ordered on a routine basis will be considered 
necessary and the medication benefits to the patient will supersede study participation, thus making the 
candidate ineligible. Prescription pain medications ordered on an as needed basis are acceptable if the 
participant states they anticipate they would not be requiring the medication or accept abstinence from 
the medication for the first 2-3 days of the study, until Visit 2 is completed. Any question by the IHB 
Study Nurses concerning the appropriateness of a current subject medication will be discussed with the 
principal investigator and /or associate investigator prior to enrollment in the study.
 
The IHB Study Nurses will also advise the candidate that all over- the-counter medications need to be 
avoided or reviewed and approved by research staff for anti-inflammatory or pain relieving properties 
prior to use. The IHB Study Nurses will contact the PI or AI for any questions or clarification as needed. 
Any new prescription medications started after the start of the study will be considered necessary and 
the benefits to the patient will supersede the study. Ineligible candidates will be counseled that they are 
ineligible for participation in the trial and referred to back to their providers to follow their usual protocols 
for influenza vaccine receipt.
 
Reference
 
Micromedex® 2.0, (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. 
Available at: http://www.micromedexsolutions.com/ (cited July 10, 2015)  Retrieved from : http://www.
micromedexsolutions.com/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/B29A35
/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/ABCEE6/ND_PG/evidencexpert/ND_B
/evidencexpert/ND_P/evidencexpert/PFActionId/evidencexpert.DoIntegratedSearch?
SearchTerm=Ibuprofen&fromInterSaltBase=true&false=null&false=null&=null#
 
U.S. Food and Drug Administration, (07/17/2015) FDA Drug Safety Communication: FDA strengthens 
warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or 
. Retrieved from http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm
strokes
 
Vaccine Injection Technique:
Injectable immunobiologics should be administered where local, neural, vascular, or tissue injury is 
unlikely. Use of longer needles has been associated with less redness or swelling than occurs with shorter 
needles because of injection into deeper muscle mass. Appropriate needle length depends on age and 
body mass. Injection technique is the most important parameter to ensure efficient intramuscular 
vaccine delivery.  For all intramuscular injections, the needle should be long enough to reach the muscle 
mass and prevent vaccine from seeping into subcutaneous tissue, but not so long as to involve 
underlying nerves, blood vessels, or bone. Vaccinators should be familiar with the anatomy of the area 
into which they are injecting vaccine. Intramuscular injections are administered at a 90-degree angle to 
the skin, preferably into the anterolateral aspect of the thigh or the deltoid muscle of the upper arm, 
depending on the age of the patient. A decision on needle size and site of injection must be made for 
each person on the basis of the size of the muscle, the thickness of adipose tissue at the injection site, 
the volume of the material to be administered, injection technique, and the depth below the muscle 
surface into which the material is to be injected. Aspiration before injection of vaccines is not necessary 
because no large blood vessels are present at the recommended injection sites. All adults who weigh < 


130 lbs. (< 60 kg), a -inch needle is sufficient to ensure intramuscular injection in the deltoid muscle if 
the injection is made at a 90-degree angle and the tissue is not bunched. For men and women who 
weigh 130-152 lbs. (60-70 kg), a 1-inch needle is sufficient. For women who weigh 152-200 lbs. (70-90 
kg) and men who weigh 152-260 lbs. (70-118 kg), a 1- to 1½ -inch needle is recommended. For women 
who weigh >200 lbs. (>90 kg) or men who weigh >260 lbs. (>118 kg), a 1½-inch needle is 
recommended.
 
All vaccinators will have a completed Injectable Influenza Vaccine Administration Competency 
assessment.  Needle selection will be based on CDC weight recommendations.
The vaccine will be shaken thoroughly and administered immediately using aseptic technique.
Intramuscular injections are administered at a 90-degree angle to the skin to the deltoid muscle of the 
upper arm. No aspiration will be performed.
 
Reference
Centers for Disease Control and Prevention. General Recommendations on Immunization. MMWR 2011;60
(2):15-16.
 
Human Biological Specimens:
Tissue (blood, blood cells) specimens will be collected at study site(s) under informed 
consent.   Approximately 20mL (1.5 tablespoon) of whole blood will be drawn over two time points from 
each study participant.  Whole blood will be collected in red top vacutainer tubes with clot 
activator.  Each tube will be spun down in the centrifuge to separate the serum from red blood 
cells.  Serum will be collected and aliquots will be prepared for laboratory testing.  Hemagglutinin 
Inhibition Antibody Titer testing will be performed by the Viral and Rickettsial Diseases Department at 
Naval Medical Research Center (NMRC) in Silver Spring, MD.  Any remaining serum at NMRC will be 
destroyed following completion of assay testing and analysis.
 
At time of enrollment, a unique study identification number (SID) will be assigned to each 
participant.  Personal identifiers will not be included on any specimen labels to protect the identity of all 
participants.  The label will include the SID, date of specimen collection, visit number, and Need Less 
Pain Study ID number. DHA-IHB study staff will transport frozen serum samples to Womack Army 
Medical Center (WAMC) Laboratory.  WAMC laboratory staff will receive, package, and ship frozen serum 
samples on dry ice to NMRC via courier service (e.g., FedEx). 
 
Participants can give an informed consent to approve or disapprove the use of their specimens for future 
clinical investigation studies.  If a study participant gives permission for their serum to be stored and 
used for future research studies, the study must be an IRB approved addendum, amendment, or 
protocol.  Subjects that give approval for future use will not be contacted or re-consented. The 
specimens will be stored at a DHA-IHB study site repository. Specimens from a study participant who 
does not give consent for future will not be stored at a DHA-IHB study site repository after study is 
complete.   These specimens will be destroyed after all testing for this study is complete.  Participants, 
under informed consent, are advised as to how they may have their sample destroyed at any time by 
contacting the Principal Investigator or other designated study team members.   All participants have the 
right to withdraw from the study at any time.   If this occurs, any specimens that are available will be 
destroyed.  Data that has been collected will be maintained in the study records. 
 
When the laboratory testing is complete, results will be sent, listed by subject ID number, to DHA-IHB 
study staff via email or fax.  Identifying information will not be shared with NMRC.
 
Serum Testing
Hemagglutinin Inhibition Assays (HAI) will be run on serum collected at Visit 1 and Visit 3 at Naval 
Medical Research Center (NMRC) under the direction of Maya Williams, Ph.D. LCDR, MSC, or her 
replacement.  Specimens from both time points will be paired to run on the same assay.  HAI testing will 
utilize strains matching those included in the inactivated influenza virus vaccine that year (strains will 
change annually to match IIV vaccine strains). 
 
Influenza virus particles have an envelope protein called hemagglutinin which binds to sialic acid 
receptors on cells.  The virus will also bind to red blood cells causing the formation of a lattice.  This 
process is called Hemagglutination, and is the basis of a rapid assay to determine levels of influenza 
virus present in a sample.  To conduct the assay, two-fold serial dilutions of a virus are prepared, mixed 
with a specific amount of red blood cells, and added to the wells of a plastic tray.  The red blood cells 
that are not bound by influenza virus sink to the bottom of a well and form a button.  The red blood cells 
that are attached to the virus particles form a lattice that coats the well.  (Influenza hemagglutinin 
inhibition assay, 2009, par 2).
 
The basis of the hemagglutinin inhibition assay is that antibodies to influenza virus will prevent 
attachment of the virus to red blood cells.   The highest dilution of serum that prevents hemagglutinin is 
called the HI titer of the serum.  If the serum contains no antibodies that react with the influenza strain, 
then hemagglutinin will be observed in all wells.  Likewise, if antibodies to the virus are present, 
hemagglutinin will not be observed until the antibodies are sufficiently diluted.  (Influenza hemagglutinin 


inhibition assay, 2009, par 5). Hemagglutinin measures the relative concentration of antibody in serum 
and is expressed as Titer. (Immunology Laboratory: Hemagglutinin).
 
Whole Blood Lactate  Testing (DHA-IHB Study Site)
A Lactate meter will be used to test the exercise group for lactate readings.   Two lactate tests will be 
performed for the exercise group at Visit 1, both pre and post Influenza vaccination.  The first lactate 
reading will be taken after the blood draw.  Residual blood from the serum collection will be used for 
the  lactate testing if possible; however, a finger stick specimen may be required if this is not 
successful.   Approximately 5uL of blood is collected for the lactate test.  The second lactate reading will 
be obtained from a fingerstick from the hand opposite to the vaccination arm, ideally within 3-8 minutes 
after the study subject completes pushups.  
 
Lactate is mainly produced in muscle cells, erythrocytes and brain cells and is metabolized by the 
liver.  Lactate, presented as an anion in blood, is an end product of anaerobic glucose metabolism and 
plays an important role in acid-base balance in the body.  Lactate is used as a biochemical indicator of 
lactic acidosis.  As lactate concentration increases in blood during exercises due to lack of oxygen, lactate 
can be measured to evaluate physical performance or to establish a proper intensity of 
exercise.  (Kawachi 1989, Kinoshita 1995, Westgren 1995, and Shimojo 1993).
 
Change in lactate can be found in light and moderate exercise.  In performing a maximal exertion effort 
lasting 30-120 seconds peak values of 15-25mmol/L may be observed 3-8 minutes post-exercise with 
POC testing (Goodwin, Harris, Hernandez & Gladden, 2007).  The lactate analyzer, which uses microliters 
of blood, will help provide a measure of muscle exertion by the exercise intervention group. 
 
Specimen Tracking and Storage at Study Site
Study participants that give informed consent for future use of serum will be stored at a DHA-IHB 
repository.  Electronic inventory of samples will be maintained in the DHA-IHB Specimen Tracker 
application.  Specimens will be identified by the unique SID assigned to the participant.  Specimen 
Tracker will capture the location of each tube by SID and display each specimen’s freezer location, 
specimen type, visit number 1 or 3, date of collection and consent for future use.
 
Specimens will be stored indefinitely after the completion of this study unless a subject requests the 
destruction of his/her specimens.  A subject may request in writing to the Principal Investigator his/her 
desire to have specimens destroyed. 
 
Sample Shipment
As mentioned above, Womack Army Medical Center Laboratory will ship specimens to Naval Medical 
Research Center Head, Viral and Rickettsial Diseases Department at Naval Medical Research Center 
(NMRC) in Silver Spring, MD, annually for the duration of the protocol.  The specimens will be shipped 
frozen on dry ice via courier service.  Each specimen will be labeled with a unique study ID number and 
protocol study code. 
 
Reference
 
Virology.ws. Influenza hemagglutinin inhibition assay. (2015). Available at: http://www.virology.ws/2009
/05/27/influenza-hemaglutinin-inhibition-assay/. Accessed August 12, 2015.
 
Medicine.mcgill.ca. Immunology Laboratory: Hemaglutinin. (2015). Available at: http://www.medicine.
mcgill.ca/physio/vlab/immun/hemag.htm. Accessed August 12, 2015.
 
Goodwin, M., Harris, J., Hernandez, A., & Gladden, L. (2007). Blood Lactate Measurements and Analysis 
during Exercise: A Guide for Clinicians. 
, (4), 558-569.
Journal of Diabetes Science and Technology 1
 
Owles, W. (1930). Alterations in the lactic acid content of the blood as a result of light exercise, and 
associated changes in the co 2 -combining power of the blood and in the alveolar co 2 pressure. The 
, 
(2), 214-237.
Journal of Physiology 69
 
Lactate Pro Test Strip Instructions:
 
Kawachi M, (1989). Lactate. 
 47:439-495.
Japanese Clinical Medicine,
 
Kinoshita K, Maeda E., & Yoshida S. (1995).  The measurements of blood lactate concentration and its 
age change in days on healthy infant. 
 43: 1071-1076.
Japan Journal of Clinical Pathology,
 
Westgren, M., Divon, M., Horal, M., Ingemarsson, I., Kublickas, M., Shimojo, N., & Nordström, L. (1995). 
Routine measurements of umbilical artery lactate levels the prediction of perinatal outcome. American 
, 
(5), 1416-1422.
Journal Of Obstetrics And Gynecology 173
 
Shimojo N, Naka K., Uenoyama H., Yoshioka K, & Okuda K (1993). Electrochemical assay system with 
single use electrode strip for measuring lactate in whole blood. 
, 39: 2312-2314.
Clinical Chemistry


 
 
 
 
 
10.2  Data Collection:
Describe all the data variables, information to be collected, the source of the data, and how the data will 
be operationally measured.
Brighton’s case definition of pain describes pain that develops in response to a vaccine at or near an injection 
site as “immunization site pain” (Gidudu, Walco et al., 2012). This includes “acute” pain in response to the 
needle and “delayed” which develops in minutes to hours following vaccination and acute pain.  It does not 
include myalgia or arthralgia pain.
 
There are three levels of diagnostic certainty and pain is differentiated as:
1. Persistent including at rest
2. Pain with movement or touch
3. Pain with impact on functioning.
 
Specific pain assessment tools which vary by age Group are recommended by Brighton for evaluation and 
study of immunization pain. Brighton acknowledges these tools have limited validation for delayed pain but 
they state they are currently the best available and would be useful for this application. The Brief Pain 
Inventory  (BPI) is a recommended numerical pain scale tool and Su, et al., (2000) validated  the tool for 
measuring injection site pain in a randomized double blind placebo controlled clinical trial. This 
study  randomized participants to one of five vaccine regimens including a saline control. Pain assessment 
was made at eight time points over a two day period after injection.
 
The Brighton Collaboration also has developed case definitions for swelling, induration and local reactions 
differentiated into 3 levels of diagnostic certainty. (Gidudu, Kohl, et al., 2008, Kohl, et al. 2007, Kohl, et al., 
2007). The measurement tools the collaboration developed for collecting data for each case definition 
developed by Brighton will be utilized. The tools have been adapted to reduce redundancy.
 
 
References:
Gidudu, Jane, Kohl, Katrin S., Halperin, Scott, Hammer, Sandra Jo, Heath, Paul, Hennig, Renald et al. 
(2008).  A local reaction at or near injection site: Case definition and guidelines for collection, analysis 
.  Vaccine 26 (2008) 6800-6813.
and presentation of immunization safety data
 
Gidudu, Jane F., Kohl, Katrin S., Halperin, Scott A., Hammer, Sandra Jo, Heath, Paul, Hennig, Renald et 
al. (2008).  A local reaction at or near injection site: Case definition and guidelines for collection, analysis 
 Vaccine 26(2008) 6800-6813.
and presentation of immunization safety data. 
 
Gidudu, Jane F., Walco, Gary, A., Taddio, Anna, Zempsky, William T., Halperin, Scott A., Calugar, Angela 
et al. (2012). Immunization site pain: Case definition and guidelines for collection, analysis, and 
. Vaccine 30(2012) 4558-4577.
presentation of immunization safety data
 
 
Kohl, Katrin S., Walop, Wikke, Gidudu, Jane, Ball, Leslie, Halperin, Scott, Hammer, Sandra Jo et. al. 
(2007). Swelling at or near injection site: Case definition and guidelines for the collection, analysis and 
Vaccine 25 (2007) 5858-5874.
presentation of immunization safety data. 
 
Su, L., Tucker,R.,  Frey,S.E.,  Gress, J.O., Chan,I. S.F.,  Kuter, B.J., Guess, H.A. (2000). Measuring 
injection-site pain associated with vaccine administration in adults: a randomized, double-blind, placebo-
Journal of Epidemiology and Biostatistics. 2000, 5(6):359-365.
controlled clinical trial. 
 
Variables/Data Points:
 
Figure 1.  Table of Variables/Data Points
 
Variable
Data Source
Pain
BPI
Erythema
Collection tool, photo
Edema
Collection tool,  photo


Induration
Collection tool,  photo
Serological response to antigens
Lab serology
Exercise
Lactate, collection tool
 
10.3  At any point in the study, will you request, use, or access health information in any form, including 
verbal, hard copy and electronic?
 Yes   
 No
10.4  Review the definitions below and respond to the following two questions.  If you are not sure of the 
answers, email 
 for assistance.
DHA.PrivacyBoard@mail.mil
 
The 
 is defined as all DoD health plans and DoD health care providers 
Military Health System (MHS)
that are organized under the management authority of, or in the case of covered individual 
providers, assigned to or employed by, the Defense Health Agency (DHA), the Army, the Navy, or 
the Air Force
 
MHS workforce members are employees, volunteers, trainees, and other persons whose conduct, in 
the performance of work for the MHS, is under the direct control of the MHS, whether or not they 
are paid by the MHS.
 
MHS business associates are persons or entities that provide a service to the MHS and require 
protected health information (PHI) to provide the service.
Are you an MHS workforce member?
Yes, I am an MHS workforce member 
No, I am not an MHS workforce member 
Are you an MHS business associate?
Yes, I am an MHS business associate 
No, I am not an MHS business associate 
10.5  Have you consulted with an MHS data expert to determine the data elements required for your 
study?
Consulting with a data expert often saves time later in the compliance process because the data expert 
can advise on the data available in the numerous MHS information systems, the quality of that data and 
the methods for encrypting and collapsing data.  To schedule a consult with an MHS data expert, send 
an email to: (
)
DHA.PrivacyBoard@mail.mil
Yes, then complete the questions below according to the data consult 
No, then complete the questions below according to the best of your knowledge 
10.6  Indicate how you will request data from the MHS.  Select all that apply.
Talking with MHS health care providers or MHS health plans about specific research participants
Obtaining MHS hard copy records specific to research participants
Obtaining data from an MHS information system(s)
10.7  If you are obtaining data from an MHS information system(s), indicate whether you plan to receive 
a data extract or whether you plan to access an MHS information system directly to create a data 
set.
A data extract is when the MHS or a contractor provides the data set directly to the researcher.  When 
receiving a data set through data extract, the researcher may indicate whether the data elements should 


be provided as is, encrypted or collapsed.  In contrast to a data extract, access to an information system 
means that the researcher may directly access an MHS information system and create a data set for the 
research study
Data Extract
Access
10.8  Do you intend to request de-identified data from the MHS in your research study? 
There are different two methods for de-identifying data pursuant to HIPAA:
1) Safe Harbor Method: Removing all of the identifiers listed in Table 1 below, provided that the 
researcher does not have actual knowledge that the remaining data can be used alone or in combination 
with other information to identify the individual who is the subject of the information
2) Statistical Method: An expert, with appropriate knowledge of and experience with generally accepted 
statistical and scientific principles and methods for rendering information not individually identifiable, 
determines that the data is not individually identifiable
  Yes   
  No
10.9  Indicate the MHS information system(s) from which you will seek to obtain data
If you do not know which system(s) contains the data elements you need, refer to the Guide for DoD 
Researchers on Using MHS Data or request guidance from an MHS data expert at: DHA.
.
PrivacyBoard@mail.mil
 
Below is a list of commonly used MHS systems. If the system from which you seek to obtain data is not 
listed below, list the name of the system in the “Other MHS Systems” category below
PHI Systems:
MHS Information System
Requesting Data
: AHLTA
PII-Only Systems:
MHS Information System
Requesting Data
No records have been added
De-Identified Data & Other Systems:
Information System
Requesting Data
No records have been added
10.10  Do you intend to merge or otherwise associate the requested data with data from any sources 
outside of the MHS, including other DoD systems that are not part of the MHS?
Yes, will merge data  
No, will not merge data 
10.11  Indicate the data elements about research participants or relatives, employers, or household 
members of the research participants that you will request from MHS hard copies or from MHS 
information systems.
If you will merge data, also indicate non-MHS data elements about research participants or 
relatives, employers, or household members of the research participants that you will have access 
to in any form or medium.
Data Element(s)
MHS
Non-MHS Systems
MHS Hard Copies


1. Names
2. Postal address with 
only town, city, state 
and zip code
3. Postal address with 
all geographic 
subdivisions smaller 
than a state, including 
street address, city, 
county, precinct, zip 
code and their 
equivalent geocodes, 
except for the initial 
three digits of a zip 
code if, according to 
the current publicly 
available data from the 
Bureau of Census: 1) 
the geographic unit 
formed by combining 
all zip codes with the 
same three initial 
digits contains more 
than 20,000 people; 
and 2) the initial three 
digits of a zip code for 
all such geographic 
units containing 
20,000 or fewer people 
is changed to 000
4. Dates including all 
elements (except year) 
directly related to an 
individual, including 
birth date, admission 
date, discharge date, 
and date of death
5. Ages over 89 and all 
elements of dates 
(including year) 
indicative of such age, 
unless you will only 
request a single 
category of “age 90 or 
older”
6. Telephone numbers
7. Fax numbers
8. Electronic mail 
addresses
9. Social Security 
numbers (SSNs)
10. Medical record 
numbers


11. Health plan 
beneficiary numbers
12. Account numbers
13. Certificate/license 
numbers
14. Vehicle identifiers 
and serial numbers, 
including license plate 
numbers
15. Device identifiers 
and serial numbers
16. Web Universal 
Resource Locators 
(URLs)
17. Internet Protocol 
(IP) address numbers
18. Biometric 
identifiers, including 
finger and voice prints
19. Full-face 
photographic images 
and any comparable 
images
20. Any other unique 
identifying number, 
characteristic, or code 
(Diagnosis, DEERS ID, 
EDI-PI, Rank)
If you are obtaining SSNs, provide a justification as to why and explain why a substitute cannot be used
The study subject's Social Security number is required to process blood draw compensations through the 
military payroll system.
10.12  Do you believe it is possible for the MHS data to become identifiable because of triangulation, a 
small cell size, or any unique data element(s)?
Triangulation means using different data elements that are not themselves identifiable but that when 
combined can be used to identify an individual. For example, triangulation would use rank and race 
together to determine the identity of an individual with a particular health condition.
 
Small cell size means that there is only a small number of eligible individuals that satisfy the category 
description. Guidance for acceptable cell size is available from the Centers for Medicare and Medicaid 
Services. For example, the rank category of four star generals with a particular diagnosis may be less 
than 30, so the rank category may need to be expanded to include lower ranks.
 


A unique data element includes any unique features that are not explicitly enumerated in the categories 
of data in rows 1 – 20 of the table above (in Section 10.10), but that could be used to identify an 
individual. Unique data elements include characteristics that are not themselves identifying, such as the 
rank of general or admiral, or a race or gender, but within the context of other information could be 
identifiable.
Yes, I believe there is a reasonable possibility the MHS data will become identifiable 
No, I believe there is no reasonable possibility the MHS data will become identifiable 
10.13  Have you completed and uploaded an appropriate HIPAA document ( i.e. HIPAA Authorization will 
be obtained or Waiver/alteration of HIPAA Authorization is being requested)?
Yes 
No 
N/A 
10.14  Managing Data (Data Management and/or Sharing Plan) and/or Human Biological Specimens for 
this Study:
Include in this section the plan for acquiring data (both electronic and hard copy), access during the 
study, data/specimen storage and length of time stored, shipment/transmission, and the plan for 
storage and final disposition at the conclusion of the study. Describe any data agreements in place for 
accessing data within and/or outside of your institution (e.g., Data Sharing Agreement, Data Use 
Agreement, Business Agreements, etc.)
PHI/PII:
PHI requested is to enable the following:
1. Adult Infulenza Screening Form to determine subject is able to receive IIV (collected after subject 
is consented)
2. Documentation and tracking for safety of the subject
-to include medical record documentation the subject is taking a study medication should a 
clinical event occur
-Identification of the subject should an issue with the medication lot be identified in the future.  
3. Callback as reminder to facilitate completion of the protocol or notification of unanticipated issues
 
Specimens will be assigned a unique study identification number and will not contain any personal 
identifiers.  Electronic information will be stored on the DHA-IHB SharePoint database and is password 
protected. The SharePoint firewalls are securely managed at Fort Detrick MD. Laboratory results will be 
sent from the Naval Medical Research Center laboratory to study research staff for linkage and 
reporting.  Thus, only research staff and Investigators will be able to link blood specimens and data to a 
specific individual.  Although personal identifiers will be kept to ensure proper linkage, they are protected 
such that no individual is identified in any report. Records and computer files will be maintained securely 
in accordance with DoD regulations (NMRDCINST 5870.4).  Although subjects will not directly benefit 
from their involvement in this study, the findings may guide public health and DoD policies that will in 
turn benefit future service members.
The following procedures are in place to ensure that confidential information will not be used or abused 
in ways that might directly or indirectly harm the individuals involved:
Administrative:
a)   All Investigators and study staff will receive training in HIPAA regulation and 
procedures. Will obtain and maintain Citi-training and follow ICH-GCP and the Belmont 
Report.
b)   The PI will monitor employees to ensure that they are following proper confidentiality 
procedures by performing, at a minimum, quarterly research site visits.
c)   A quarterly review of confidentiality routines will be conducted;
d)   If employees leave the program, they will remain under obligation to protect the 
confidentiality of all data collected as part of the program.
 
Procedural:
a)   Access to PHI will be restricted to DHA-IHB investigators or by DoD provider/co-
investigators as part of treatment, and these data will not be re-used or re-disclosed to 
any other entity.


1.  
2.  
3.  
4.  
b)   Subject consent forms and records from each data source will be collected and 
assimilated by study staff in paper-based files and/or electronic files maintained at the 
clinical sites and on WAMC and DHA-IHB servers.
c)   Subject laboratory specimens being tested  will be sent by the DHA-IHB research staff 
to Naval Medical Research Center Laboratory, Silver Spring, MD, with a non-personal 
identifier (SID#) assigned by DHA-IHB investigators.  Results will be sent from the lab 
to the research staff/investigators in conjunction with the SID# via encrypted email or 
secure fax. The testing laboratory will not have access to any identifiable data.   
d)   Data utilized for this proposal consist of the minimum necessary PHI needed to 
accomplish the study goals; however, all data is assumed to be, and is treated as, PHI.
e)   All data is entered on password-protected computers.
f)   Findings will only be released as an aggregate; no individuals will be identified with the 
possible exception of any requirement to report if required by law, e.g. the financial 
remuneration if required for tax purposes or reportable abuse.
 
Physical safeguards:
The research office is located on an access controlled military installation. Study staff 
/investigators will store study files in locked metal cabinets in building C-5537 Tullidge Way, Ft 
Bragg NC 28310.
The locked cabinets are located inside the office behind locked doors. There is a security gate 
surrounding the research office that is kept locked after hours and on weekends and holidays.
Key control procedures include file keys remain in a locked box when not in use and a key 
signature accountability form is maintained.
Only investigators and research staff have access to the files.
.
 
Technical safeguards:
 
a)   All study databases will be stored on the existing DHA-IHB information systems 
network, which requires a DoD issued Common Access Card (CAC) in conjunction with a 
unique personal identification number (PIN) for access.  The DHA-IHB network security 
system will prevent all others from accessing these files.  This system meets current 
DoD data security requirements. 
b)   The Principal Investigator will grant access to the confidential database only to those 
staff members who require it. 
      c)   All data will be carefully guarded and used only to meet the stated study objectives.   
d)   Data are analyzed using only de-identified analytic data files, which will be retained for 
six years after the close of the study.
e)   There will be periodic review of the computer security procedures by DHA-IHB network 
managers including challenges of the security firewall erected to assure its integrity.
 
This study uses participant provided demographic and health data (data collection form), electronic 
military data obtained from AHLTA and laboratory results.  These data consist of the minimum necessary 
Protected Health Information (PHI) needed to accomplish the study goals; however, all data is assumed 
to be, and is treated as, PHI.
 
We will request permission from potential participants to collect PHI.  The PHI that will be collected for 
the study will be specified in the Informed Consent Form (ICF) and used with authorization from the 
subject as stipulated in the ICF.  The ICF includes the following required information: a description of the 
information to be used; the name of the person(s) requesting the use; the name of the person(s) who 
may use the requested PHI, i.e., the intended recipients; a description of each purpose of the requested 
use; the length of time that the data will be maintained, tied to an expiration date or an expiration 
event; a statement regarding the individual’s right to revoke authorization for use of PHI and whom to 
contact in writing to revoke the authorization; a statement regarding the individual’s right to inspect hard 
copies of any PHI collected and who to contact in writing to inspect the contributed data.  Original ICFs 
and data collection forms will be maintained in a locked file at the research office. The study coordinators 
will maintain study electronic files and the master enrollment file on a CAC enabled WAMC imaged 
computer. These files will be maintained and backed up on the Z:/ drive and remain under WAMC firewall 
protection.
 
Our use of PHI involves no more than minimal risk to the individuals since we will implement procedures 
to control access to the information collected.  The analytic database will not contain identifiers; instead, 
the data will be stored in conjunction with a randomly assigned subject identification number.  A 
separate database will contain the data in conjunction with PHI, which is necessary for linking data.  The 
SharePoint database is located on secure servers located at Fort Detrick, MD. Access to files containing 
PHI is restricted to approved IRB investigators and research staff.   
 


Identified data will be maintained securely at DHA-IHB both within the physical environment and IT 
environment.  Hard copies of any records will be stored in a locked file cabinet as mentioned above. All 
data are stored as password-protected files that are stripped of personal identifiers, to the extent 
possible for the research and will retain study-specific subject identification numbers. Data are managed 
and analyzed using only these de-identified data files, which will be destroyed by shredding and 
degaussing, for paper files and electronic files respectively, six years following completion of the study, 
or longer as dictated by any future required retention periods, whichever is longer.  Findings will only be 
released as an aggregate; no individuals will be identified.  Blood specimens without consent for long 
term storage will be destroyed after testing.
 
10.15  Managing Data (Data Management and/or Sharing Plan) and/or Human Biological Specimens for 
Future Research:
If the study involves collecting, storing, or banking human specimens, data, or documents (either by the 
Investigator or through an established repository) for FUTURE research, address. How the specimens
/data will be used, where and how data/specimens will be stored (including shipping procedures, storage 
plan, etc.), whether and how consent will be obtained, procedures that will fulfill subjects’ request as 
stated in the consent, whether subjects may withdraw their data/specimens from storage, whether and 
how subjects may be recontacted for future research and given the option to decline, whether there will 
be genetic testing on the specimens, who will have access to the data/specimens, and the linkage, the 
length of time that data/specimens will be stored and conditions under which data/specimens will be 
destroyed.
Specimen Tracking and Storage at Study Site
Study participants that give informed consent for future use of serum will be stored at a DHA-IHB 
repository.  Electronic inventory of samples will be maintained in the DHA-IHB Specimen Tracker 
application.  Specimens will be identified by the unique SID assigned to the participant.  Specimen 
Tracker will capture the location of each tube by SID and display each specimen’s freezer location, 
specimen type, visit number 1 or 3, date of collection and consent for future use.
 
Specimens will be stored indefinitely after the completion of this study unless a subject requests the 
destruction of his/her specimens.  A subject may request in writing to the Principal Investigator his/her 
desire to have specimens destroyed. 
11.0
 
Statistical/Data Analysis Plan
11.1  Statistical Considerations:
List the statistical methods to be used to address the primary and secondary objectives, specific aims, 
and/or research hypotheses.  Explain how missing data and outliers will be handled in the analysis.  The 
analysis plan should be consistent with the study objectives.  Include any sub-group analyses (e.g., 
gender or age group).  Specify statistical methods and variables for each analysis.  Describe how 
confounding variables will be controlled in the data analysis
DATA ANALYSIS:  The primary outcome of interest for this study is self-reported delayed pain post 
vaccine. Thus we plan to analyze differences in mean pain scores among the 3 Groups using ANOVA with 
planned comparison between the exercise condition (Group C) and the other Groups.  Repeated 
measures ANOVAs will be used to analyze pre and post vaccine differences in lactate, serological 
response to antigens, edema, and erythema.  If data fail to satisfy test assumptions such as normality, a 
log transformation or non-parametric test will be used as appropriate.  Statistically significant effects will 
be followed-up with Tukey’s HSD post hoc mean comparison.  In the event that pain data show a 
bimodal distribution, appropriate cut offs will be determined so as to create dichotomized (pain / no-
pain) scores.  In this scenario, 2 pair-wise comparisons will be made between Groups C&A and C&B using 
Chi square tests.  Demographic characteristics will be compared among Groups using a one-way ANOVA 
or Chi square test, as appropriate.  A significance level of  ≤ 0.05 will be used for all analyses. 
p
 
Figure 2.  Data Analysis Table
 
Statistical Test
Independent Variable/
Predictors Variables
Dependent Variable/
Outcome Variables
ANOVA, Chi Square
Treatment condition
Pain


1.  
2.  
Repeated Measures 
ANOVA
Treatment condition
Edema, Erythema, Lactate, Serology
 
11.2  Sample Size:
350
11.3  Total number of subjects requested (including records and specimens):
350
11.4  If you are recruiting by study arm, please identify the arms of the study and how many subjects will 
be enrolled in each arm
N/A
11.5  Please provide a justification for your sample size
Sample Size: We will enroll up to 350 participants with a goal of approximately 216 with 
complete data sets
Power Analysis: A sample size of 216 is needed for the study to yield an 86% chance of 
rejecting the null hypothesis ( <0.05), assuming a moderate effect size of 0.25. 
p
11.6  Data Analysis Plan: Complete description: Background, Objectives, Design, Step by Step how the 
project is going to be done, Data analysis plan:
DATA ANALYSIS:  The primary outcome of interest for this study is self-reported delayed pain post 
vaccine. Thus we plan to analyze differences in mean pain scores among the 3 Groups using ANOVA with 
planned comparison between the exercise condition (Group C) and the other Groups.  Repeated 
measures ANOVAs will be used to analyze pre and post vaccine differences in lactate, serological 
response to antigens, edema, and erythema.  If data fail to satisfy test assumptions such as normality, a 
log transformation or non-parametric test will be used as appropriate.  Statistically significant effects will 
be followed-up with Tukey’s HSD post hoc mean comparison.  In the event that pain data show a 
bimodal distribution, appropriate cut offs will be determined so as to create dichotomized (pain / no-
pain) scores.  In this scenario, 2 pair-wise comparisons will be made between Groups C&A and C&B using 
Chi square tests.  Demographic characteristics will be compared among Groups using a one-way ANOVA 
or Chi square test, as appropriate.  A significance level of  ≤ 0.05 will be used for all analyses. 
p
12.0
 
Participant Information
12.1  Subject Population:
Active-duty men and women who meet the study criteria at WAMC and WRNMMC will be considered for 
enrollment.
12.2  Age Range:
Check all the boxes that apply. if the age range of potential subjects (specimens, records) does not 
match the range(s) selected, please specify in the text box.
0-17
18-24


25-34
35-44
45-54
55-64
65-74
75+
12.3  Gender:
Male
Female
Other
12.4  Special categories, check all that apply
Minors /Children
Students
Employees - Civilian
Employees - Contractor
Resident/trainee
Cadets /Midshipmen
Active Duty Military Personnel
Wounded Warriors
Economically Disadvantaged Persons
Educationally Disadvantaged Persons
Physically Challenged (Physical challenges include visual and/or auditory impairment)
Persons with Impaired Decisional Capacity
Prisoners
Pregnant Women, Fetuses, and Neonates
Non-English Speakers
International Research involving Foreign Nationals - Headquarters Review is necessary
You must also consider the requirements of DoDI 3216.02, Enclosure 3, paragraph 7.e.
12.5  Inclusion Criteria:
Order 
Number
Criteria
1 
18 years of age old and older
 
2 
Active Duty Service Members
 
3 
Requiring and eligible for inactivated influenza vaccine receipt
 
4 
Be willing and able to complete the study protocol requirements
 


5 
Have a current completed Flu Screening Form to receive the influenza 
vaccination.   
 
12.6  Exclusion Criteria:
Order 
Number
Criteria
1 
Previous receipt of the current seasonal influenza vaccine.
 
2 
Receipt of any vaccine 72 hours before influenza vaccine receipt.
 
3 
Medical profile resulting in current profile exemption from PT of U2 or U3.
 
4 
Have preexisting symptoms of injury or infection or other local symptoms 
that require medical evaluation or treatment to either upper extremity
 
5 
Pregnancy
 
6 
Have a history of allergy, intolerance, stomach bleeding or other medical exclusion 
for ibuprofen?
 
7 
A history of stroke or heart disease, such as uncontrolled high blood pressure, 
heart attack or  abnormal heart beat.          
 
8 
Taking any topical or oral pain medications from the following medication classes 
in the past 24 hours prior to the start of the study: oral acetaminophen, opioids, 
tramadol, NSAID or ASA or topical pain relievers or counterirritants of menthol, 
methyl salicylate, camphor menthols, and capsaicins.
 
9 
Currently participating in any other study that asks participant to take a medicine 
or exercise.             
 
10 
Any acute or chronic illness or treatment causing immunological suppression, as 
defined by Infectious Disease Society of America (IDSA) definitions of High and 
Low level Immunosuppression (Rubin, et.al, 2013).  Any participant whose status 
is unclear or potentially immunosuppressed in the clinical judgement of the PI or 
AI will not be enrolled.
 
13.0
 
Recruitment and Consent


13.1  Please describe the recruitment process, including how subjects will be identified and selected for 
the study.
Active duty males and females 18 years of age and older eligible for annual influenza vaccine receipt.
 
(Please see section 10.1 for additional information.)
13.2  Compensation for Participation:
 
The subject will receive compensation in the amount of $50 per blood draw ($100 total); payments will 
be made via direct deposit to the subject's banking account or via $50 gift card. No compensation will be 
provided for visit #2 which does not include any type of blood sampling.
13.3  Please describe the pre-screening process. If no pre-screening, enter Not Applicable in the text 
editor
Persons wishing to be considered for participation will be screened for eligibility by the 
study personnel by completion of the Study Eligibility Screening Form (see attachment B). 
Females of childbearing age will be required to complete a pregnancy test after being 
consented. The previously completed Adult Influenza Screening forms will be reviewed by 
the study personnel, after completion of the consent form, to ensure congruence with the 
Study Eligibility Screening Form and confirm no contraindication to vaccination exists.
13.4  Consent Process:
 
Revised Common Rule, Section 219.116:  General requirements for informed consent, whether 
written or oral, are set forth in this paragraph and apply to consent obtained in accordance with the 
requirements set forth in paragraphs (b) through (d) of this section. Broad consent may be 
obtained in lieu of informed consent obtained in accordance with paragraphs (b) and (c) of this 
section only with respect to the storage, maintenance, and secondary research uses of identifiable 
private information and identifiable biospecimens.
Are you requesting a waiver or alteration of informed consent?
  Yes   
  No
Please explain the consent process:
Persons who are eligible for participation will receive counseling from the study personnel to meet the 
established guidelines for informed consent: to include a statement of the purpose, randomization 
process, use of placebo control, use of prescription dose ibuprofen, foreseeable risks, potential 
benefits, research staff contact information, rights and responsibilities, and that participation is 
voluntary. During the consenting process, subjects will be asked for contact information and consent 
to be contacted by telephone or email for clarification of medical history, and/or prior immunizations 
and/or adverse events. The subject will be informed that use of their unsecure personal email account 
is not recommended due to the potential risks of inadvertent disclosure of their personal healt 
information. They will be advised that their personal email may only be used as a last resort and with 
their written permission. The study personnel will also provide counseling and the participant will 
complete the Consent/HIPAA form.
 
Since the data and specimens collected may be of significant utility for future studies, subjects will be 
asked for consent for future study to include use of collected specimens and use of data collected. 
Subjects will be asked for permission to be contacted for future studies and the participant will have the 
option to consent or refuse permissions for future studies without effect on participation in this study. 
Subjects interested in study participation will complete the study consent/HIPAA form with required 
initials, signature, and date.
13.5  DoDI 3216.02 requires an ombudsman to be present during recruitment briefings when research 
involves greater than minimal risk and recruitment of Service members occurs in a group setting. If 
applicable, you may nominate an individual to serve as the ombudsman.
N/A 
Propose ombudsman 


1.  
2.  
3.  
4.  
5.  
6.  
7.  
1.  
13.6  Withdrawal from Study Participation:
Explain the process for withdrawal and specify whether or not the subjects will be given the opportunity 
to withdraw their data their data/specimens in the event they wish to withdraw from the study
 
 
All participants have the right to withdraw from the study at any time.  If this occurs, any specimens that 
are available will be destroyed. Data that has been collected will be maintained in the study records.
14.0
 
Risks and Benefits
14.1  
Risks of Harm:
Identify all research-related risks of harm to which the subject will be exposed for each research 
procedure or intervention as a result of participation in this study.  Consider the risks of breach of 
confidentiality, psychological, legal, social, and economic risks as well as physical risks.  Do not describe 
risks from standard care procedures; only describe risks from procedures done for research purposes
Identify all research-related risks of harm to which the subject will be exposed for each research 
procedure or intervention as a result of participation in this study. Consider the risks of breach of 
confidentiality, psychological, legal, social, and economic risks as well as physical risks. Do not 
describe risks from standard care procedures; only describe risks from procedures done for 
research purposes
 
 
RISKS TO SUBJECTS
The risk to human subjects is likely minimal because:
 
The NSAID intervention is of minimal duration in a low risk group for receipt of this pharmacologic 
agent.
The vaccine is not part of the study, however an adverse event to the vaccine may occur, and the 
subject will be referred to DHA-IHB for evaluation and management.
The participants could experience increased pain associated with performance of compound 
exercise of pushups.
The participants could experience an adverse effect associated with the POC finger stick, or 
venipuncture including pain, or infection which is rare.
The participants could experience a decrease in expected immune response, in particular those 
assigned to the oral NSAID arm, potentially decreasing influenza disease protection. The clinical 
significance in terms of actual disease risk due to decreased titers is unknown and has not been 
studied. In previous trials which measured serological response to full dose vaccine, participants 
still achieved protective titers. Serological markers are also only one component of the immune 
response to antigen and a decrease may not represent increased disease risk.
The participants assigned to the exercise arm could potentially sustain physical injury from 
engaging in the pushup type compound exercise. This risk is no more likely than the participant’s 
everyday routine fitness activities as the pushup type compound exercise is routinely performed 
by the participants and part of themilitary PFT.
The participants assigned to the oral NSAID arm could experience an adverse effect associated 
with this medication, such as a hypersensitivity reaction. Ibuprofen was selected due to its 
ubiquitous use both prescription and over- the- counter in lower doses such that allergy or 
intolerance would likely already be known. The adverse effect potential is minimal due to the 
short duration of therapy and the safety profile of the medication. Most significant reactions are 
associated with longer term use than the 48 hour protocol or in higher risk populations such as 
elderly. See section 7.34 study medications for additional discussion
 
h
testing will be completed as part of eligibility screening.
. Pregnancy 
 
RISKS:
 
An inadvertent disclosure could occur.


The individuals participating in this RCT could experience a loss of privacy/confidentiality of enrollmen in 
the study, particularly the exercise intervention group who could be observed performing pushups post 
vaccine re
14.2  
Measures to Minimize Risks of Harm (Precautions, safeguards):
For each research procedure or intervention, describe all measures to minimize and/or eliminate risk of 
harms to subjects and study personnel
Vaccine Injection Technique:
Injectable immunobiologics should be administered where local, neural, vascular, or tissue injury 
is unlikely. Use of longer needles has been associated with less redness or swelling than occurs 
with shorter needles because of injection into deeper muscle mass. Appropriate needle length 
depends on age and body mass. Injection technique is the most important parameter to ensure 
efficient intramuscular
vaccine delivery. For all intramuscular injections, the needle should be long enough to reach the 
muscle mass and prevent vaccine from seeping into subcutaneous tissue, but not so long as to 
involve underlying nerves, blood vessels, or bone. Vaccinators should be familiar with the 
anatomy of the area into which they are injecting vaccine. Intramuscular injections are 
administered at a 90-degree angle to the skin, preferably into the anterolateral aspect of the 
thigh or the deltoid muscle of the upper arm, depending on the age of the patient. A decision on 
needle size and site of injection must be made for each person on the basis of the size of the 
muscle, the thickness of adipose tissue at the injection site, the volume of the material to be 
administered, injection technique, and the depth below the muscle surface into which the 
material is to be injected. Aspiration before injection of vaccines is not necessary because no 
large blood vessels are present at the recommended injection sites. All adults who weigh
<130 lbs. (<60 kg), a -inch needle is sufficient to ensure intramuscular injection in the deltoid 
muscle if the injection is made at a 90-degree angle and the tissue is not bunched. For men and 
women who weigh 130-152 lbs. (60-70 kg), a 1-inch needle is sufficient. For women who weigh 
152-200 lbs. (70-90 kg) and men who weigh 152-260 lbs. (70-118 kg), a 1- to 1½ -inch needle 
is recommended. For women who weigh >200 lbs. (>90 kg) or men who weigh >260 lbs. (>118 
kg), a 1½-inch needle is recommended.
 
All vaccinators will have a completed Injectable Influenza Vaccine Administration 
Competency assessment. Needle selection will be based on CDC weight 
recommendations.
 
The vaccine will be shaken thoroughly and administered immediately using aseptic technique. 
Intramuscular injections are administered at a 90-degree angle to the skin to the deltoid muscle of 
the upper arm. No aspiration will be performed.
14.3  
Confidentiality Protections (for research records, data and/or specimens):
Describe in detail the plan to maintain confidentiality of the research data, specimens, and records 
throughout the study and at its conclusion (e.g., destruction, long term storage, or banking). Explain the 
plan for securing the data (e.g., use of passwords, encryption, secure servers, firewalls, and other 
appropriate methods). If data will be shared electronically with other team members/collaborators 
outside the institution, describe the method of transmission and safeguards to maintain confidentiality. 
Explain whether this study may collect information that State or Federal law requires to be reported to 
other officials or ethically requires action, e.g., child or spouse abuse
 
Specimens will be assigned a unique study identification number and will not contain any 
personal identifiers. Electronic information will be stored on the DHA-IHB SharePoint database 
and is password protected. The SharePoint firewalls are securely managed at Fort Detrick MD. 
Laboratory results will be sent from the Naval Medical Research Center laboratory to study 
research staff for linkage and reporting. Thus, only research staff and Investigators will be able 
to link blood specimens and data to a
specific individual. Although personal identifiers will be kept to ensure proper linkage, they are 
protected such that no individual is identified in any report. Records and computer files will be 
maintained securely in accordance with DoD regulations (NMRDCINST 5870.4).
14.4  
Potential Benefits:


1.  
1.  
1.  
2.  
3.  
4.  
Describe any real and potential benefits of the research to the subject and any potential benefits to a 
specific community or society
If the individuals in the research are considered experimental subjects (per 10 USC 980), and they 
cannot provide their own consent, the protocol must describe the intent to directly benefit all subjects
BENEFITS:
 
Although there are no direct benefits to the participants, the information may assist in
determining best practice recommendations concerning use of exercise or NSAIDS 
associated with vaccine receipt for mitigation of common adverse effects and serologic 
impact of those recommendations
Addressing vaccine concerns may decrease vaccine hesitancy, increase acceptability and 
tolerability increasing overall vaccine rates, especially for optional vaccines. This improves and 
promotes public health goals of increased vaccination rates and improves health of populations.
 
MEDICAL APPLICATION: Address gaps in current literature concerning:
Efficacy of exercise as an intervention to decrease post immunization site local inflammation 
effects
Efficacy of NSAIDS as an intervention to decrease post immunization site local inflammation 
effects
Serological effects of exercise on immunization response
Serological effects of NSAID on immunization response
14.5  
Privacy for Subjects:
Describe the measures to protect subject’s privacy during recruitment, the consent process, and all 
research activities, etc.
Subjects will be consented and complete all study documents in one of the study nurse's private offices 
and all other procedures will be performed in the study team's examination room behind closed doors. 
Recruitment will be done via Intranet advertisement with DRP approved flyer, through posting of same 
study flyers in WRNMMC clinics, during open recruitment in lobby of building 19, and through word of 
mouth referrals.
14.6  
Incidental or Unexpected Findings:
Describe the plan to address incidental findings and unexpected findings about individuals from 
screening to the end of the subject’s participation in the research. In cases where the subject could 
possibly benefit medically or otherwise from the information, state whether or not the results of 
screening, research participation, research tests, etc., will be shared with subjects or their primary care 
provider. State whether the researcher is obligated or mandated to report results to appropriate military 
or civilian authorities and explain the potential impact on the subject
Findings will only be released as an aggregate; no individuals will be identified with the possible 
exception of any requirement to report if required by law, e.g. the financial remuneration if required for 
tax purposes or reportable abuse.
15.0
 
Study Monitoring


1.  
2.  
15.1  Your study requires either Data and Safety Monitoring Plan (DSMP) or a Data and Safety Monitoring 
Board (DSMB).
DSMP 
DSMB 
Both 
Not Applicable 
A DSMP should describe the plan to monitor the data to verify that the data are collected and analyzed 
as specified in the protocol. Include who will conduct the monitoring, what will be monitored, and the 
frequency of monitoring. It should also include the plan to ensure the safety of subjects
 
 
Safety Review Plan and Monitoring
 
Purpose: Oversight of participant safety includes review of adverse events as well as study progress, data 
integrity and study outcomes.
 
Safety and study progress reviews
 
The Principal Investigator and/or his/her designee will review the adverse events log on a semi-annual 
basis to ensure adverse events are being reported to the WRNMMC IRB in accordance with the IRB-
approved protocol and in a timely manner.  Furthermore, the Principal Investigator will review adverse 
events to determine whether rates are consistent with pre-study assumptions.
 
The Principal Investigator and/or his/her designee will review study progress, to include recruitment 
and enrollment rates, retention, data integrity, and protocol adherence, on a semi-annual basis.  This 
individual will offer recommendations for improving enrollment and retention, when applicable.
 
What precautions will you take to protect the confidentiality of research source documents (Case 
Report Forms, questionnaires, etc.), the research data file, and the master code (if any)?
               
To protect the confidentiality of these data, unique study identification numbers will be created and assigned 
to each subject.  The linkage of study identification numbers with personal identifiers will be stored in the 
master data roster and will only be accessible by the Principal Investigator and designated Associated 
Investigators/Team Members. 
               
The datasets used for purposes of review and analysis will contain the study identification number without 
personal identifying information. Paper copies will be stored in secure, locked file cabinets within the IHB 
offices.
 
At time of enrollment, a unique study identification number (SID) will be assigned to each participant.  Personal 
identifiers will not be included on any specimen labels to protect the identity of all participants.  The label will 
include information such as the SID, date of specimen collection, and visit number. Tissue (blood, blood cells) 
specimens will be collected at study site(s) under informed consent.  Hemagglutinin Inhibition Antibody Titer 
testing will be performed by the Viral and Rickettsial Diseases Department at Naval Medical Research Center 
(NMRC) in Silver Spring, MD.  Protocol laboratory staff will package and ship frozen serum samples on dry ice to 
NMRC via courier service (e.g., FedEx). Any remaining serum at NMRC will be destroyed following completion of 
assay testing and analysis.
 
Participants can give informed consent to approve or disapprove the use of their specimens for future clinical 
investigation studies.  If a study participant gives permission for their serum to be stored and used for future 
research studies, the study must be an IRB approved addendum, amendment, or protocol.  The specimens will be 
stored at a DHA-IHB tissue repository. Specimens from a study participant who does not give consent for future 
will not be stored at a DHA-IHB study site repository after study is complete.  These specimens will be destroyed 
after all testing for this study is complete.  Participants, under informed consent, are advised as to how they may 
have their sample destroyed at any time by contacting the Principal Investigator or other designated study team 
members.  All participants have the right to withdraw from the study at any time.  If this occurs, any specimens 
that are available will be destroyed.  Data that has been collected will be maintained in the study records. 
 
When the laboratory testing is complete, results will be sent, listed by subject ID number, to DHA-IHB study staff 
via email or fax.  Identifying information will not be shared with NMRC.
16.0
 


Reportable Events
16.1  Reportable Events: Consult with the research office at your institution to ensure requirements are 
met. Describe plans for reporting unexpected adverse events and unanticipated problems. Address 
how unexpected adverse events will be identified, who will report, how often adverse events and 
unanticipated problems will be reviewed to determine if any changes to the protocol or consent 
form are needed and the scale that will be used to grade the severity of the adverse event. 
Consult with the research office at your institution to ensure requirements are met
 
• Describe plans for reporting expected adverse events. Identify what the expected adverse events will 
be for this study, describe the likelihood (frequency, severity, reversibility, short-term management and 
any long-term implications of each expected event)
 
• Describe plans for reporting unexpected adverse events and unanticipated problems. Address how 
unexpected adverse events will be identified, who will report, how often adverse events and 
unanticipated problems will be reviewed to determine if any changes to the research protocol or consent 
form are needed and the scale that will be used to grade the severity of the adverse event
Reportable Events include adverse events (AE), serious adverse events (SAE), unanticipated 
problems involving risks to subjects or others (UPIRTSO), and protocol deviations occurring at 
the WRNMMC or the WAMC study site will be reported IAW RHC-A P & P. All reporting 
requirements are listed in the PI agreement.
 
17.0
 
Equipment/non-FDA Regulated Devices
17.1  Does the study involve the use of any unique non-medical devices/equipment?
  Yes   
  No
18.0
 
FDA-Regulated Products
18.1  Will any drugs, dietary supplements, biologics, or devices be utilized in this study?
Drugs
Dietary Supplements
Biologics
Devices
N/A
18.2  Drugs, Dietary Supplements and Biologics/Vaccines details:
Are drug(s) in this research being used in accordance to the approved labeling?
Are drug(s) in this research being used in a manner other than its approved labeling?
Enter Dietary Supplements and Biologics/Vaccines in the Drug Information table. Complete all relevant 
fields in the table (“Protocol Drug Details” screen). If the question is not relevant, leave the question 
blank and/or do not change the default selection.
View 
Details
Drug Name
FDA Approved
A new drug or a 
new use of 
approved drug:
IND Number
Trade Drug 
Name: IBUPROFEN


Generic Drug 
Name:
Investigational 
Drug Name:
Yes 
No 
 
Trade Drug Name:
IBUPROFEN 
Generic Drug Name:
 
Investigational Drug Name:
 
Identify the name of the 
manufacturer or source of 
investigational drug/biologic:
US Compounding  
Is the drug supplied at no cost?
Yes  
Is the Drug FDA Approved:
Yes  
Is this a new drug or a new use 
of an already approved drug
No  
Is an IND necessary
No  
IND Number
 
Who holds the IND:
N/A  
IND details:
 
If FDA Approved and an IND is 
not required, Please provide a 
rationale for exemption:
 
Are you currently using this IND 
in another research project?
No  
If yes, list the IRB Number(s):
 
Dose Range:
 
Frequency:
every 8 hrs x 48 hrs  
Route of administration:
by mouth  
Will the investigational pharmacy 
be dispensing?
Yes  
If the source is not a FDA 
licensed facility, provide details 
regarding the purity, quality, 
stability and sterility of the 
investigational drug/biologic:
US Compounding is an FDA registered 503b outsourcing facility 
with P-CAB accreditation.  
Identify who will be preparing the 
investigational drug/biologic for 
administration and describe in 
detail how it will be prepared:
The research pharmacist at WAMC, Sherry Lamberth, will receive 
and prepare the ibuprofen and placebo from US Compounding. 
She will utilize the SID enrollment list to randomize the 
products.  
Indication(s) under Investigation:
Pain  
Where will the drug be stored
WAMC pharmacy and the research office  
Drug Storage Restrictions 
(including temperature, etc.):
Product is stored in a pharmacy bottle with a child proof cap 
inside a locked cabinet in a clean and environmentally controlled 
atmosphere at ambient temperature between 64-72 degrees 
Fahrenheit. (+ or - 5 degrees)  
Administration Instructions:
The study drug is used in accordance with it's FDA approved 
labeling. (2) 400mg capsules will be taken by mouth with food 3 
times a day for 48 hours.  
Possible Untoward Effects, Their 
Symptoms & Treatment:
See ibuprofen/placebo package insert and investigators 
brochure.  
Potential or Actual Antidotes for 
Excessive or Adverse Drug Effect:
See ibuprofen/placebo package insert and investigators 
brochure  
Contraindications and 
See ibuprofen/placebo package insert and investigators 


Interactions, If Known:
brochure  
Investigators Authorized to 
Prescribe:
Laurie Housel, FNP and Bruce McClenathan, MD  
Trade Drug 
Name:
Placebo 
capsule
Generic Drug 
Name:
Investigational 
Drug Name:
No 
No 
 
Trade Drug Name:
Placebo capsule 
Generic Drug Name:
 
Investigational Drug Name:
 
Identify the name of the 
manufacturer or source of 
investigational drug/biologic:
US Compounding  
Is the drug supplied at no cost?
Yes  
Is the Drug FDA Approved:
No  
Is this a new drug or a new use 
of an already approved drug
No  
Is an IND necessary
No  
IND Number
 
Who holds the IND:
N/A  
IND details:
 
If FDA Approved and an IND is 
not required, Please provide a 
rationale for exemption:
Placebo  
Are you currently using this IND 
in another research project?
No  
If yes, list the IRB Number(s):
 
Dose Range:
 
Frequency:
every 8 hours x 48 hours  
Route of administration:
by mouth  
Will the investigational pharmacy 
be dispensing?
Yes  
If the source is not a FDA 
licensed facility, provide details 
regarding the purity, quality, 
stability and sterility of the 
investigational drug/biologic:
US Compounding is an FDA registered 503b outsourcing facility 
with P-CAB accreditation.  
Identify who will be preparing the 
investigational drug/biologic for 
administration and describe in 
detail how it will be prepared:
The research pharmacist at WAMC, Sherry Lamberth, will receive 
and prepare the ibuprofen and placebo from US Compounding. 
She will utilize the SID enrollment list to randomize the 
products.  
Indication(s) under Investigation:
Pain  
Where will the drug be stored
WAMC pharmacy and research office  
Drug Storage Restrictions 
(including temperature, etc.):
Product is stored in a pharmacy bottle with a child proof cap 
inside a locked cabinet in a clean and environmentally controlled 
atmosphere at ambient temperature between 64-72 degrees 
Fahrenheit. (+ or - 5 degrees)  
Administration Instructions:
Placebo contains no lactose and no active ingredients. It will be 
randomized by SID. Two capsules will be given by mouth at the 
study site with a snack and water. Subjects will be advised to 


take two capsules every 8 hours until gone.  
Possible Untoward Effects, Their 
Symptoms & Treatment:
None (Placebo contains no lactose)  
Potential or Actual Antidotes for 
Excessive or Adverse Drug Effect:
None  
Contraindications and 
Interactions, If Known:
None  
Investigators Authorized to 
Prescribe:
Laurie Housel, FNP and Dr. Bruce McClenathan, MD  
18.4  Reporting Requirements for FDA-regulated research under IND and IDE:
Describe the process for complying with FDA regulatory requirements for adverse event reporting and 
adverse device effects reporting to the sponsor
N/A; this is not a FDA-regulated research under IND and IDE.
18.5  Sponsor (organization/institution/company):
N/A
If applicable, provide sponsor contact information:
19.0
 
Research Registration Requirements
19.1  ClinicalTrials.gov Registration:
Registration is not required 
Registration pending 
Registration complete 
“NCT” number:
NCT02807623
19.2  Defense Technical Information Center Registration (Optional):
Registration is not required 
Registration pending 
Registration complete 
20.0
 
References and Glossary
20.1  References:
REFERENCES:
 
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Andrew, et al. (2010). The effects of vaccine timing on the efficacy of an acute eccentric exercise 
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Immunity
 
Chambers, C., Taddio, A., Uman, L., & McMurtry, C. (2009). Psychological interventions for reducing pain 
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Cobb, Jean, E., & Cohen, Lindsey, L. (2009). A randomized controlled trial of the Shotblocker for children’
s immunization distress  
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Cohen Reis, E., & Holubkov, R. (1997). Vapocoolant Spray Is Equally Effective as EMLA Cream in 
Reducing Immunization Pain in School-aged Children. 
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PEDIATRICS 100
 
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Vaccination Adverse Reactions and Antibody Response in Children: A Systematic Review. 
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Plos ONE 9
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Defense Health Agency Immunization Health Care Branch. US Army Medical Command, Falls Church, VA.
 
Díez-Domingo, J., Planelles, M., Baldó, J., Ballester, A., Núñez, F., Jubert, A., & Dominguez-Granados, R. 
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Prophylactic and Therapeutic Paracetamol Treatment during Vaccination on Hepatitis B Antibody Levels in 
Adults: Two Open-Label, Randomized Controlled Trials. 
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Plos ONE 9
 
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Flublock US Package Insert. October  2014. Protein Sciences Corporation
 
Flucelvax US Package Insert. March 2014. Novartis Vaccines and Diagnostics, Inc.
 
Flulavel US Package Insert. May 2014. GlaxoSmithKline.
 
Fluvirin US Package Insert. April 2014. Novartis Vaccines and Diagnostics, Inc.
 
Fluzone US Package Insert. June 2014. Sanofi Pasteur, Inc.
 
Gidudu, J., Kohl, K., Halperin, S., Hammer, S., Heath, P., & Hennig, R. et al. (2008). A local reaction at 
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immunization safety data. 
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Vaccine 26
 
Gidudu, J., Walco, G., Taddio, A., Zempsky, W., Halperin, S., & Calugar, A. et al. (2012). Immunization 
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data. 
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Vaccine 30
 
Edwards, K., & Booy, R. (2013). Effects of exercise on vaccine-induced immune responses. Human 
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Vaccines & Immunotherapeutics 9
 


Edwards, K., Burns, V., Adkins, A., Carroll, D., Drayson, M., & Ring, C. (2008). Meningococcal A 
Vaccination Response is Enhanced by Acute Stress in Men. 
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Psychosomatic Medicine 70
[abstract].
 
Edwards, K., Burns, V., Allen, L., McPhee, J., Bosch, J., & Carroll, D. et al. (2007). Eccentric exercise as 
an adjuvant to influenza vaccination in humans. 
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Brain, Behavior, and Immunity 21
 
Edwards, K., Burns, V., Reynolds, T., Carroll, D., Drayson, M., & Ring, C. (2006). Acute stress exposure 
prior to influenza vaccination enhances antibody response in women. 
, 
(
Brain, Behavior, And Immunity 20
2), 159-168.
 
Edwards, K., Campbell, J., Ring, C., Drayson, M., Bosch, J., & Downes, C. et al. (2010). Exercise 
intensity does not influence the efficacy of eccentric exercise as a behavioural adjuvant to vaccination. Br
, 
(4), 623-630.
ain, Behavior, And Immunity 24
 
Edwards, K., Pung, M., Tomfohr, L., Ziegler, M., Campbell, J., Drayson, M., & Mills, P. (2012). Acute 
exercise enhancement of pneumococcal vaccination response: A randomised controlled trial of weaker 
and stronger immune response. 
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Vaccine 30
 
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Pneumococcal antibody responses in elite swimmers  
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244.
 
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adverse reactions following DTP vaccination
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. Eastern Journal of Medicine
 
Hogan, M., Kikuta, A., & Taddio, A. (2010). A systematic review of measures for reducing injection pain 
during adult immunization. 
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Vaccine 28
 
Irwin, M.R., Olmstead, R. & Oxman, M.N. (2007).  Augmenting Immune responses to varicella zoster 
virus in older adults: A randomized controlled trial of Tai Chi  
 
. Journal of the American Geriatrics Society
55(4), 511-517.
 
Jackson, Lisa A., Dunstan, M., Starkovich, P., Dunn, J., Yu, O., Nelson, J.C. et al. (2006). Prophylaxis 
with acetaminophen or ibuprofen for prevention of local reactions to the fifth diphtheria-tetanus toxoids-
acellular pertussis vaccination: a randomized controlled trial
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. PEDIATRICS,
 
Keylock, K., Lowder, T., Leifheit, K., Cook, M., Mariani, R., & Ross, K. et al. (2006). Higher antibody, but 
not cell-mediated, responses to vaccination in high physically fit elderly. 
, 
Journal of Applied Physiology 10
(3), 1090-1098.
2
 
Kohl, K., Walop, W., Gidudu, J., Ball, L., Halperin, S., & Hammer, S. et al. (2007). Induration at or near 
injection site: Case definition and guidelines for collection, analysis, and presentation of immunization 
safety data. 
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Vaccine 25
 
Kohl, K., Walop, W., Gidudu, J., Ball, L., Halperin, S., & Hammer, S. et al. (2007). Swelling at or near 
injection site: Case definition and guidelines for collection, analysis and presentation of immunization 
safety data. 
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(31), 5858-5874.
Vaccine 25
 
Kohut, M., L., Arntson, B., A., Wanglok, L., Rozebloom, K., Yoon, K.-J., Cunnick, J. E., McElhaney, J. 
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Gerontology
 
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for adolescents immunization pain
.  March 25 (1):19-26.
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intervention and the antibody response to pneumococcal vaccination in women.  
 
Psychosomatic Medicine
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following aerobic exercise: can a brisk walk enhance antibody response to pneumococcal and influenza 
vaccination?  
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Brain, Behavior and Immunity
 
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discomfort after injection: a randomized controlled trial  
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childhood immunization.
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Vapocoolant Quickly and Effectively Reduces Vaccine-associated Pain: Results of a Randomized, Single-
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Nikashima, Y., Harada, M., Okayama, M., & Kajii, E. (2013). Analgesia for pain during subcutaneous 
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Medicine
 
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Exercise Training Extends Influenza Vaccine Seroprotection in Sedentary Older Adults: The Immune 
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Journal Of The American Geriatrics Society
 
Yalçın, S., Gümüš, A., & Yurdakök, K. (2008). Prophylactic use of acetaminophen in children vaccinated 
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World Journal Of Pediatrics 4
20.2  Abbreviations and Acronyms: