Clinical trial NCT02807623: Do NSAIDS or Executing Exercise Decrease Local Erythema, Site Swelling & Pain After INoculation
Official title: "Do NSAIDS or Executing Exercise Decrease Local Erythema, Site Swelling & Pain After INoculation: the NEED LESS PAIN Study"
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Immune System and Related Disorders
Lead sponsor: Womack Army Medical Center
Sponsor class: FED
Collaborators: name: United States Department of Defense
First posted: 2016-06-21
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: Inclusion Criteria:

Must:

1. Be Active Duty Service Members.
2. at least 18 years of age or older.
3. Be requiring and eligible for inactivated influenza vaccine receipt.
4. Be willing and able to complete the study protocol requirements.
5. Have a current Flu Screening Form with medical clearance to receive the influenza vaccination.

Exclusion Criteria:

Must Not:

1. Have already received influenza vaccine for the current season.
2. Have received any type of vaccine in the previous 72 hours.
3. Be on a medical profile resulting in current profile exemption from Physical Training of Upper 2 or Upper 3. (Upper extremity injury or illness)
4. Have preexisting symptoms of injury or infection or other local symptoms that would interfere with site assessment.
5. Be pregnant.
6. Have a history of allergy, intolerance, stomach bleeding or other medical exclusion for ibuprofen.
7. Have a history of stroke or coronary artery disease, such as uncontrolled high blood pressure or abnormal heart beat.
8. Has taken 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, nonsteroidal anti-inflammatory drug (NSAID) or acetylsalicylic acid (ASA) or topical pain relievers or counterirritants of menthol, methyl salicylate, camphor menthols, and capsaicins.
9. Have any chronic or acute illness or treatment causing immunological suppression such as current oral steroid therapy, malignancy or chemotherapy or lung disease. (not including controlled asthma)
10. Currently participating in any other study

    -

Primary outcomes:
measure: Level of Pain
timeFrame: baseline, 48-72 hours and at 21-28 days ( 3 points )
Secondary outcomes:
measure: Serologic Response - A/California/7/2009
timeFrame: Day 0 and between 21-28 days (2 points)
measure: Serologic Response - A/Hong Kong / 4801/2014
timeFrame: Day 0 and between 21-28 days (2 points)
measure: Serologic Response - B/Phuket/3073/2013
timeFrame: Day 0 and between 21-28 days (2 points)
measure: Serologic Response - B/Brisbane/60/2008
timeFrame: Day 0 and between 21-28 days (2 points)
measure: Participants With Erythema
timeFrame: baseline, 48- 72 hours, 21-28 days (3 points)
measure: Participants With Edema
timeFrame: baseline, 48-72 hours, and 21- 28 days (3 points)
Other outcomes:
measure: Lactate
timeFrame: Immediately prior to Influenza vaccine and 3-8 minutes after Influenza vaccine was administered and after push-ups were completed.
Locations:
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Fort Bragg
country: United States
facility: Womack Army Medical Center
state: North Carolina
Study officials:
affiliation: Defense Health Agency Immunization Healthcare Branch
name: Laurie A. Housel, MSN,FNP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Abbott K, Fowler-Kerry S. The use of a topical refrigerant anesthetic to reduce injection pain in children. J Pain Symptom Manage. 1995 Nov;10(8):584-90. doi: 10.1016/0885-3924(95)00086-0.
citation: Abuelkheir M, Alsourani D, Al-Eyadhy A, Temsah MH, Meo SA, Alzamil F. EMLA(R) cream: a pain-relieving strategy for childhood vaccination. J Int Med Res. 2014 Apr;42(2):329-36. doi: 10.1177/0300060513509473. Epub 2014 Feb 5.
citation: Berberich FR, Landman Z. Reducing immunization discomfort in 4- to 6-year-old children: a randomized clinical trial. Pediatrics. 2009 Aug;124(2):e203-9. doi: 10.1542/peds.2007-3466. Epub 2009 Jul 13.
citation: Bruunsgaard H, Hartkopp A, Mohr T, Konradsen H, Heron I, Mordhorst CH, Pedersen BK. In vivo cell-mediated immunity and vaccination response following prolonged, intense exercise. Med Sci Sports Exerc. 1997 Sep;29(9):1176-81. doi: 10.1097/00005768-199709000-00009.
citation: Campbell JP, Edwards KM, Ring C, Drayson MT, Bosch JA, Inskip A, Long JE, Pulsford D, Burns VE. 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 Behav Immun. 2010 Feb;24(2):236-42. doi: 10.1016/j.bbi.2009.10.001. Epub 2009 Oct 8.
citation: Chambers CT, Taddio A, Uman LS, McMurtry CM; HELPinKIDS Team. Psychological interventions for reducing pain and distress during routine childhood immunizations: a systematic review. Clin Ther. 2009;31 Suppl 2:S77-S103. doi: 10.1016/j.clinthera.2009.07.023.
citation: Cobb JE, Cohen LL. A randomized controlled trial of the ShotBlocker for children's immunization distress. Clin J Pain. 2009 Nov-Dec;25(9):790-6. doi: 10.1097/AJP.0b013e3181af1324.
citation: Cohen Reis E, Holubkov R. Vapocoolant spray is equally effective as EMLA cream in reducing immunization pain in school-aged children. Pediatrics. 1997 Dec;100(6):E5. doi: 10.1542/peds.100.6.e5.
citation: Das RR, Panigrahi I, Naik SS. The effect of prophylactic antipyretic administration on post-vaccination adverse reactions and antibody response in children: a systematic review. PLoS One. 2014 Sep 2;9(9):e106629. doi: 10.1371/journal.pone.0106629. eCollection 2014.
citation: Dilli D, Kucuk IG, Dallar Y. Interventions to reduce pain during vaccination in infancy. J Pediatr. 2009 Mar;154(3):385-90. doi: 10.1016/j.jpeds.2008.08.037. Epub 2008 Oct 11.
citation: Doedee AM, Boland GJ, Pennings JL, de Klerk A, Berbers GA, van der Klis FR, de Melker HE, van Loveren H, Janssen R. Effects of prophylactic and therapeutic paracetamol treatment during vaccination on hepatitis B antibody levels in adults: two open-label, randomized controlled trials. PLoS One. 2014 Jun 4;9(6):e98175. doi: 10.1371/journal.pone.0098175. eCollection 2014.
citation: Gidudu JF, Walco GA, Taddio A, Zempsky WT, Halperin SA, Calugar A, Gibbs NA, Hennig R, Jovancevic M, Netterlid E, O'Connor T, Oleske JM, Varricchio F, Tsai TF, Seifert H, Schuind AE; Brighton Immunization Site Pain Working Group. Immunization site pain: case definition and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine. 2012 Jun 22;30(30):4558-77. doi: 10.1016/j.vaccine.2012.03.085. Epub 2012 Apr 18. No abstract available.
citation: Gidudu J, Kohl KS, Halperin S, Hammer SJ, Heath PT, Hennig R, Hoet B, Rothstein E, Schuind A, Varricchio F, Walop W; Brighton Collaboration Local Reactions Working Group for a Local Reaction at or near Injection Site. A local reaction at or near injection site: case definition and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine. 2008 Dec 9;26(52):6800-13. doi: 10.1016/j.vaccine.2008.10.006. Epub 2008 Oct 23.
citation: Edwards KM, Booy R. Effects of exercise on vaccine-induced immune responses. Hum Vaccin Immunother. 2013 Apr;9(4):907-10. doi: 10.4161/hv.23365. Epub 2013 Jan 14.
citation: Edwards KM, Burns VE, Adkins AE, Carroll D, Drayson M, Ring C. Meningococcal A vaccination response is enhanced by acute stress in men. Psychosom Med. 2008 Feb;70(2):147-51. doi: 10.1097/PSY.0b013e318164232e. Epub 2008 Feb 6.
citation: Edwards KM, Burns VE, Allen LM, McPhee JS, Bosch JA, Carroll D, Drayson M, Ring C. Eccentric exercise as an adjuvant to influenza vaccination in humans. Brain Behav Immun. 2007 Feb;21(2):209-17. doi: 10.1016/j.bbi.2006.04.158. Epub 2006 Jul 7.
citation: Edwards KM, Burns VE, Reynolds T, Carroll D, Drayson M, Ring C. Acute stress exposure prior to influenza vaccination enhances antibody response in women. Brain Behav Immun. 2006 Mar;20(2):159-68. doi: 10.1016/j.bbi.2005.07.001. Epub 2005 Aug 15.
citation: Edwards KM, Campbell JP, Ring C, Drayson MT, Bosch JA, Downes C, Long JE, Lumb JA, Merry A, Paine NJ, Burns VE. Exercise intensity does not influence the efficacy of eccentric exercise as a behavioural adjuvant to vaccination. Brain Behav Immun. 2010 May;24(4):623-30. doi: 10.1016/j.bbi.2010.01.009. Epub 2010 Jan 25.
citation: Edwards KM, Pung MA, Tomfohr LM, Ziegler MG, Campbell JP, Drayson MT, Mills PJ. Acute exercise enhancement of pneumococcal vaccination response: a randomised controlled trial of weaker and stronger immune response. Vaccine. 2012 Oct 5;30(45):6389-95. doi: 10.1016/j.vaccine.2012.08.022. Epub 2012 Aug 22.
citation: Gleeson M, Pyne DB, McDonald WA, Clancy RL, Cripps AW, Horn PL, Fricker PA. Pneumococcal antibody responses in elite swimmers. Clin Exp Immunol. 1996 Aug;105(2):238-44. doi: 10.1046/j.1365-2249.1996.d01-752.x.
citation: Taddio A, Lord A, Hogan ME, Kikuta A, Yiu A, Darra E, Bruinse B, Keogh T, Stephens D. A randomized controlled trial of analgesia during vaccination in adults. Vaccine. 2010 Jul 19;28(32):5365-9. doi: 10.1016/j.vaccine.2010.05.015. Epub 2010 May 16.
citation: Hogan ME, Kikuta A, Taddio A. A systematic review of measures for reducing injection pain during adult immunization. Vaccine. 2010 Feb 10;28(6):1514-21. doi: 10.1016/j.vaccine.2009.11.065. Epub 2009 Dec 8.
citation: Irwin MR, Olmstead R, Oxman MN. Augmenting immune responses to varicella zoster virus in older adults: a randomized, controlled trial of Tai Chi. J Am Geriatr Soc. 2007 Apr;55(4):511-7. doi: 10.1111/j.1532-5415.2007.01109.x.
citation: Jackson LA, Dunstan M, Starkovich P, Dunn J, Yu O, Nelson JC, Rees T, Zavitkovsky A. Prophylaxis with acetaminophen or ibuprofen for prevention of local reactions to the fifth diphtheria-tetanus toxoids-acellular pertussis vaccination: a randomized, controlled trial. Pediatrics. 2006 Mar;117(3):620-5. doi: 10.1542/peds.2005-1217.
citation: Keylock KT, Lowder T, Leifheit KA, Cook M, Mariani RA, Ross K, Kim K, Chapman-Novakofski K, McAuley E, Woods JA. Higher antibody, but not cell-mediated, responses to vaccination in high physically fit elderly. J Appl Physiol (1985). 2007 Mar;102(3):1090-8. doi: 10.1152/japplphysiol.00790.2006. Epub 2006 Nov 9.
citation: Kohl KS, Walop W, Gidudu J, Ball L, Halperin S, Hammer SJ, Heath P, Hennig R, Rothstein E, Schuind A, Varricchio F; Brighton Collaboration Local Reactions Working Group for Induration at or near Injection Site. Induration at or near injection site: case definition and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine. 2007 Aug 1;25(31):5839-57. doi: 10.1016/j.vaccine.2007.04.062. Epub 2007 May 8. No abstract available.
citation: Kohl KS, Walop W, Gidudu J, Ball L, Halperin S, Hammer SJ, Heath P, Varricchio F, Rothstein E, Schuind A, Hennig R; Brighton Collaboration Local Reaction Working Group for Swelling at or near Injection Site. Swelling at or near injection site: case definition and guidelines for collection, analysis and presentation of immunization safety data. Vaccine. 2007 Aug 1;25(31):5858-74. doi: 10.1016/j.vaccine.2007.04.056. Epub 2007 May 11. No abstract available.
citation: Kohut ML, Arntson BA, Lee W, Rozeboom K, Yoon KJ, Cunnick JE, McElhaney J. Moderate exercise improves antibody response to influenza immunization in older adults. Vaccine. 2004 Jun 2;22(17-18):2298-306. doi: 10.1016/j.vaccine.2003.11.023.
citation: Kohut ML, Cooper MM, Nickolaus MS, Russell DR, Cunnick JE. Exercise and psychosocial factors modulate immunity to influenza vaccine in elderly individuals. J Gerontol A Biol Sci Med Sci. 2002 Sep;57(9):M557-62. doi: 10.1093/gerona/57.9.m557.
citation: Kristjansdottir O, Kristjansdottir G. Randomized clinical trial of musical distraction with and without headphones for adolescents' immunization pain. Scand J Caring Sci. 2011 Mar;25(1):19-26. doi: 10.1111/j.1471-6712.2010.00784.x.
citation: Long JE, Ring C, Bosch JA, Eves F, Drayson MT, Calver R, Say V, Allen D, Burns VE. A life-style physical activity intervention and the antibody response to pneumococcal vaccination in women. Psychosom Med. 2013 Oct;75(8):774-82. doi: 10.1097/PSY.0b013e3182a0b664. Epub 2013 Aug 6.
citation: Long JE, Ring C, Drayson M, Bosch J, Campbell JP, Bhabra J, Browne D, Dawson J, Harding S, Lau J, Burns VE. Vaccination response following aerobic exercise: can a brisk walk enhance antibody response to pneumococcal and influenza vaccinations? Brain Behav Immun. 2012 May;26(4):680-7. doi: 10.1016/j.bbi.2012.02.004. Epub 2012 Feb 22.
citation: Maiden MJ, Benton GN, Bourne RA. Effect of warming adult diphtheria-tetanus vaccine on discomfort after injection: a randomised controlled trial. Med J Aust. 2003 May 5;178(9):433-6. doi: 10.5694/j.1326-5377.2003.tb05284.x.
citation: Manley J, Taddio A. Acetaminophen and ibuprofen for prevention of adverse reactions associated with childhood immunization. Ann Pharmacother. 2007 Jul;41(7):1227-32. doi: 10.1345/aph.1H647. Epub 2007 May 22.
citation: Mawhorter S, Daugherty L, Ford A, Hughes R, Metzger D, Easley K. Topical vapocoolant quickly and effectively reduces vaccine-associated pain: results of a randomized, single-blinded, placebo-controlled study. J Travel Med. 2004 Sep-Oct;11(5):267-72. doi: 10.2310/7060.2004.19101.
citation: Nakashima Y, Harada M, Okayama M, Kajii E. Analgesia for pain during subcutaneous injection: effectiveness of manual pressure application before injection. Int J Gen Med. 2013 Sep 25;6:817-20. doi: 10.2147/IJGM.S50125. eCollection 2013.
citation: Nilsson S, Forsner M, Finnstrom B, Morelius E. Relaxation and guided imagery do not reduce stress, pain and unpleasantness for 11- to 12-year-old girls during vaccinations. Acta Paediatr. 2015 Jul;104(7):724-9. doi: 10.1111/apa.13000. Epub 2015 Apr 22.
citation: Pascoe AR, Fiatarone Singh MA, Edwards KM. The effects of exercise on vaccination responses: a review of chronic and acute exercise interventions in humans. Brain Behav Immun. 2014 Jul;39:33-41. doi: 10.1016/j.bbi.2013.10.003. Epub 2013 Oct 11.
citation: Porter CK, Bowens MJ, Tribble DR, Putnam SD, Sanders JW, Riddle MS. Attitudes towards vaccines and infectious disease risk among U.S. troops. Hum Vaccin. 2008 Jul-Aug;4(4):298-304. doi: 10.4161/hv.4.4.5802. Epub 2008 Feb 27. No abstract available.
citation: Prymula R, Siegrist CA, Chlibek R, Zemlickova H, Vackova M, Smetana J, Lommel P, Kaliskova E, Borys D, Schuerman L. Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. Lancet. 2009 Oct 17;374(9698):1339-50. doi: 10.1016/S0140-6736(09)61208-3.
citation: Ranadive SM, Cook M, Kappus RM, Yan H, Lane AD, Woods JA, Wilund KR, Iwamoto G, Vanar V, Tandon R, Fernhall B. Effect of acute aerobic exercise on vaccine efficacy in older adults. Med Sci Sports Exerc. 2014 Mar;46(3):455-61. doi: 10.1249/MSS.0b013e3182a75ff2.
citation: Rose MA, Juergens C, Schmoele-Thoma B, Gruber WC, Baker S, Zielen S. An open-label randomized clinical trial of prophylactic paracetamol coadministered with 7-valent pneumococcal conjugate vaccine and hexavalent diphtheria toxoid, tetanus toxoid, 3-component acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b vaccine. BMC Pediatr. 2013 Jun 21;13:98. doi: 10.1186/1471-2431-13-98.
citation: Russell K, Nicholson R, Naidu R. Reducing the pain of intramuscular benzathine penicillin injections in the rheumatic fever population of Counties Manukau District Health Board. J Paediatr Child Health. 2014 Feb;50(2):112-7. doi: 10.1111/jpc.12400. Epub 2013 Oct 18.
citation: Shah V, Taddio A, Rieder MJ; HELPinKIDS Team. Effectiveness and tolerability of pharmacologic and combined interventions for reducing injection pain during routine childhood immunizations: systematic review and meta-analyses. Clin Ther. 2009;31 Suppl 2:S104-51. doi: 10.1016/j.clinthera.2009.08.001.
citation: Schuler PB, Leblanc PA, Marzilli TS. Effect of physical activity on the production of specific antibody in response to the 1998-99 influenza virus vaccine in older adults. J Sports Med Phys Fitness. 2003 Sep;43(3):404.
citation: Sparks L. Taking the "ouch" out of injections for children. Using distraction to decrease pain. MCN Am J Matern Child Nurs. 2001 Mar-Apr;26(2):72-8. doi: 10.1097/00005721-200103000-00005.
citation: Taddio A, Appleton M, Bortolussi R, Chambers C, Dubey V, Halperin S, Hanrahan A, Ipp M, Lockett D, MacDonald N, Midmer D, Mousmanis P, Palda V, Pielak K, Riddell RP, Rieder M, Scott J, Shah V. Reducing the pain of childhood vaccination: an evidence-based clinical practice guideline (summary). CMAJ. 2010 Dec 14;182(18):1989-95. doi: 10.1503/cmaj.092048. Epub 2010 Nov 22. No abstract available.
citation: Taddio A, Chambers CT, Halperin SA, Ipp M, Lockett D, Rieder MJ, Shah V. Inadequate pain management during routine childhood immunizations: the nerve of it. Clin Ther. 2009;31 Suppl 2:S152-67. doi: 10.1016/j.clinthera.2009.07.022.
citation: Taddio A, Ilersich AL, Ipp M, Kikuta A, Shah V; HELPinKIDS Team. Physical interventions and injection techniques for reducing injection pain during routine childhood immunizations: systematic review of randomized controlled trials and quasi-randomized controlled trials. Clin Ther. 2009;31 Suppl 2:S48-76. doi: 10.1016/j.clinthera.2009.07.024.
citation: Woods JA, Keylock KT, Lowder T, Vieira VJ, Zelkovich W, Dumich S, Colantuano K, Lyons K, Leifheit K, Cook M, Chapman-Novakofski K, McAuley E. Cardiovascular exercise training extends influenza vaccine seroprotection in sedentary older adults: the immune function intervention trial. J Am Geriatr Soc. 2009 Dec;57(12):2183-91. doi: 10.1111/j.1532-5415.2009.02563.x.
citation: Yalcin SS, Gumus A, Yurdakok K. Prophylactic use of acetaminophen in children vaccinated with diphtheria-tetanus-pertussis. World J Pediatr. 2008 May;4(2):127-9. doi: 10.1007/s12519-008-0025-7.
citation: Afluria US Package Insert for 2015-2016. 2015. bioCSL version 44. Retrieved from http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM263239.pdf
citation: Defense Health Agency (2004). Clinical guidelines for managing adverse events after vaccination. Defense Health Agency Immunization Health Care Branch. US Army Medical Command, Falls Church, VA.
citation: Díez-Domingo, J., Planelles, M., Baldó, J., Ballester, A., Núñez, F., Jubert, A., & Dominguez-Granados, R. (1998). Ibuprofen prophylaxis for adverse reactions to diphtheria-tetanus-pertussis vaccination: a randomized trial. Current Therapeutic Research, 59(8), 579-588.
citation: Fluarix US Package Insert. 2014. GlaxoSmithKline.
citation: Fluzone US Package Insert. June 2014. Sanofi Pasteur, Inc.
citation: Flublock US Package Insert. October 2014. Protein Sciences Corporation
citation: Flucelvax US Package Insert. March 2014. Novartis Vaccines and Diagnostics, Inc.
citation: Flulavel US Package Insert. May 2014. GlaxoSmithKline.
citation: Fluvirin US Package Insert. April 2014. Novartis Vaccines and Diagnostics, Inc.
citation: Hayat, H., Khan, Parwez S. & Hayat, G. (2011). The effect of prophylactic paracetamol administration on adverse reactions following DTP vaccination. Eastern Journal of Medicine 16, 258-260.
citation: Schuler PB, Lloyd LK, Leblanc PA, Clapp TA, Abadie BR, Collins RK. The effect of physical activity and fitness on specific antibody production in college students. J Sports Med Phys Fitness. 1999 Sep;39(3):233-9.
citation: Whitham M, Blannin AK. The effect of exercise training on the kinetics of the antibody response to influenza vaccination. J Sports Sci. 2003 Dec;21(12):991-1000. doi: 10.1080/0264041031000140464.