Immune System and Related Disorders
Conditions
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.
Interventions
DRUGIbuprofen
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.
BEHAVIORALCompound Exercise of Push-ups
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.
DRUGoral placebo
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.
Sponsors
United States Department of Defense
Womack Army Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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 \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Level of Pain | baseline, 48-72 hours and at 21-28 days ( 3 points ) | Level of Pain will be measured by validated pain scale, using a scale of 0 ( best, no pain) to 10 (worst, as bad as imaginable, completely interferes). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serologic Response - A/California/7/2009 | Day 0 and between 21-28 days (2 points) | Baseline lab specimen (visit 1, day 0, before immunization) and repeated between 21-28 days (visit 3) after immunization to measure serologic response |
| Serologic Response - A/Hong Kong / 4801/2014 | Day 0 and between 21-28 days (2 points) | Baseline lab specimen (visit 1, day 0, before immunization) and repeated between 21-28 days (visit 3) after immunization to measure serologic response |
| Serologic Response - B/Phuket/3073/2013 | Day 0 and between 21-28 days (2 points) | Baseline lab specimen (visit 1, day 0, before immunization) and repeated between 21-28 days (visit 3) after immunization to measure serologic response |
| Participants With Erythema | baseline, 48- 72 hours, 21-28 days (3 points) | Reddening of the skin at vaccination site reported as the total number of participants with erythema over the duration of the study. |
| Participants With Edema | baseline, 48-72 hours, and 21- 28 days (3 points) | Swelling at vaccination site |
| Serologic Response - B/Brisbane/60/2008 | Day 0 and between 21-28 days (2 points) | Baseline lab specimen (visit 1, day 0, before immunization) and repeated between 21-28 days (visit 3) after immunization to measure serologic response |
Other
| Measure | Time frame | Description |
|---|---|---|
| Lactate | Immediately prior to Influenza vaccine and 3-8 minutes after Influenza vaccine was administered and after push-ups were completed. | A Lactate meter was used to test the exercise group for lactate readings. Two lactate tests was performed for the exercise group at Visit 1, both pre and post Influenza vaccination. The first lactate reading was taken after the blood draw.The second lactate reading was obtained from a fingerstick from the hand opposite to the vaccination arm, ideally within 3-8 minutes after the study subject completes pushups. |
Countries
United States
Participant flow
Recruitment details
A total of 315 active-duty US Military Service Members due to receive injectable influenza vaccine (IIV) were recruited via flyers or verbal briefing from the Fort Bragg, North Carolina 82'nd Airborne Soldier Readiness Center and Walter Reed National Military Medical Center between 9/19/2016 and 11/6/2018.
Pre-assignment details
Of these 315 subjects, 15 were excluded due to the following reasons: 4 did not meet inclusion criteria, 2 declined to participate, and 9 are identified as other reasons. 300 were randomized to 1 of 3 arms. However, only 233 of the 300 returned for follow-up visits. Thus results are based on data from those 233 participants with completed data.
Participants by arm
| Arm | Count |
|---|---|
| Ibuprofen 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.
Ibuprofen: 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. | 75 |
| Placebo 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.
oral placebo: 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. | 81 |
| Compound Exercise of Push-ups Randomized study participants assigned to Group C will perform an exercise intervention of push-ups immediately after influenza vaccine receipt.
Compound Exercise of Push-ups: 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. | 77 |
| Total | 233 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Drug intolerance | 0 | 1 | 0 |
| Overall Study | incomplete blood draw | 0 | 2 | 1 |
| Overall Study | Lost to Follow-up | 23 | 18 | 22 |
Baseline characteristics
| Characteristic | Ibuprofen | Placebo | Compound Exercise of Push-ups | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 75 Participants | 81 Participants | 77 Participants | 233 Participants |
| Age, Continuous | 26.13 years STANDARD_DEVIATION 6.119 | 25.33 years STANDARD_DEVIATION 5.239 | 25.95 years STANDARD_DEVIATION 5.426 | 25.79 years STANDARD_DEVIATION 5.583 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 48 Participants | 61 Participants | 53 Participants | 162 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 18 Participants | 17 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 2 Participants | 7 Participants | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 22 Participants | 13 Participants | 45 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 27 Participants | 20 Participants | 24 Participants | 71 Participants |
| Race (NIH/OMB) White | 38 Participants | 39 Participants | 40 Participants | 117 Participants |
| Region of Enrollment United States | 75 participants | 81 participants | 77 participants | 233 participants |
| Sex: Female, Male Female | 11 Participants | 16 Participants | 11 Participants | 38 Participants |
| Sex: Female, Male Male | 64 Participants | 65 Participants | 66 Participants | 195 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 98 | 0 / 100 | 0 / 102 |
| other Total, other adverse events | 0 / 98 | 1 / 100 | 0 / 102 |
| serious Total, serious adverse events | 0 / 98 | 0 / 100 | 0 / 102 |
Outcome results
Primary
Level of Pain
Level of Pain will be measured by validated pain scale, using a scale of 0 ( best, no pain) to 10 (worst, as bad as imaginable, completely interferes).
Time frame: baseline, 48-72 hours and at 21-28 days ( 3 points )
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ibuprofen | Level of Pain | Visit 3 | .28 units on a scale | Standard Deviation 1.122 |
| Ibuprofen | Level of Pain | Visit 2 | .56 units on a scale | Standard Deviation 1.626 |
| Ibuprofen | Level of Pain | Visit 1 | .39 units on a scale | Standard Deviation 1.384 |
| Placebo | Level of Pain | Visit 3 | .06 units on a scale | Standard Deviation 0.401 |
| Placebo | Level of Pain | Visit 2 | .22 units on a scale | Standard Deviation 0.741 |
| Placebo | Level of Pain | Visit 1 | .19 units on a scale | Standard Deviation 0.713 |
| Compound Exercise of Push-ups | Level of Pain | Visit 3 | .13 units on a scale | Standard Deviation 0.745 |
| Compound Exercise of Push-ups | Level of Pain | Visit 2 | .19 units on a scale | Standard Deviation 0.65 |
| Compound Exercise of Push-ups | Level of Pain | Visit 1 | .14 units on a scale | Standard Deviation 0.639 |
Secondary
Participants With Edema
Swelling at vaccination site
Time frame: baseline, 48-72 hours, and 21- 28 days (3 points)
Population: Statistical analysis of participants with edema post-vaccination was not performed due to no cases of edema reported by participants or observed by research staff.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibuprofen | Participants With Edema | 0 Participants |
| Placebo | Participants With Edema | 0 Participants |
| Compound Exercise of Push-ups | Participants With Edema | 0 Participants |
Secondary
Participants With Erythema
Reddening of the skin at vaccination site reported as the total number of participants with erythema over the duration of the study.
Time frame: baseline, 48- 72 hours, 21-28 days (3 points)
Population: Statistical analysis of participants with erythema post-vaccination was not performed due to no cases of erythema reported by participants or observed by research staff.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibuprofen | Participants With Erythema | 0 Participants |
| Placebo | Participants With Erythema | 0 Participants |
| Compound Exercise of Push-ups | Participants With Erythema | 0 Participants |
Secondary
Serologic Response - A/California/7/2009
Baseline lab specimen (visit 1, day 0, before immunization) and repeated between 21-28 days (visit 3) after immunization to measure serologic response
Time frame: Day 0 and between 21-28 days (2 points)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ibuprofen | Serologic Response - A/California/7/2009 | Followup (between 21-28 days, visit 3) | 343.03 Titer | Standard Deviation 216.797 |
| Ibuprofen | Serologic Response - A/California/7/2009 | Baseline (day 0, visit 1) | 216.75 Titer | Standard Deviation 182.072 |
| Placebo | Serologic Response - A/California/7/2009 | Followup (between 21-28 days, visit 3) | 239.25 Titer | Standard Deviation 120.223 |
| Placebo | Serologic Response - A/California/7/2009 | Baseline (day 0, visit 1) | 171.00 Titer | Standard Deviation 105.97 |
| Compound Exercise of Push-ups | Serologic Response - A/California/7/2009 | Baseline (day 0, visit 1) | 214.80 Titer | Standard Deviation 171.742 |
| Compound Exercise of Push-ups | Serologic Response - A/California/7/2009 | Followup (between 21-28 days, visit 3) | 345.09 Titer | Standard Deviation 217.495 |
Secondary
Serologic Response - A/Hong Kong / 4801/2014
Baseline lab specimen (visit 1, day 0, before immunization) and repeated between 21-28 days (visit 3) after immunization to measure serologic response
Time frame: Day 0 and between 21-28 days (2 points)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ibuprofen | Serologic Response - A/Hong Kong / 4801/2014 | Baseline (day 0, visit 1) | 221.09 Titer | Standard Deviation 263.64 |
| Ibuprofen | Serologic Response - A/Hong Kong / 4801/2014 | Followup (between 21-28 days, visit 3) | 296.66 Titer | Standard Deviation 299.001 |
| Placebo | Serologic Response - A/Hong Kong / 4801/2014 | Baseline (day 0, visit 1) | 177.78 Titer | Standard Deviation 165.489 |
| Placebo | Serologic Response - A/Hong Kong / 4801/2014 | Followup (between 21-28 days, visit 3) | 243.13 Titer | Standard Deviation 203.461 |
| Compound Exercise of Push-ups | Serologic Response - A/Hong Kong / 4801/2014 | Baseline (day 0, visit 1) | 149.22 Titer | Standard Deviation 146.387 |
| Compound Exercise of Push-ups | Serologic Response - A/Hong Kong / 4801/2014 | Followup (between 21-28 days, visit 3) | 232.58 Titer | Standard Deviation 176.394 |
Secondary
Serologic Response - B/Brisbane/60/2008
Baseline lab specimen (visit 1, day 0, before immunization) and repeated between 21-28 days (visit 3) after immunization to measure serologic response
Time frame: Day 0 and between 21-28 days (2 points)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ibuprofen | Serologic Response - B/Brisbane/60/2008 | Baseline (day 0, visit 1) | 26.09 Titer | Standard Deviation 31.308 |
| Ibuprofen | Serologic Response - B/Brisbane/60/2008 | Followup (between 21-28 days, visit 3) | 34.09 Titer | Standard Deviation 29.977 |
| Placebo | Serologic Response - B/Brisbane/60/2008 | Baseline (day 0, visit 1) | 17.41 Titer | Standard Deviation 12.271 |
| Placebo | Serologic Response - B/Brisbane/60/2008 | Followup (between 21-28 days, visit 3) | 25.47 Titer | Standard Deviation 18.3 |
| Compound Exercise of Push-ups | Serologic Response - B/Brisbane/60/2008 | Baseline (day 0, visit 1) | 26.00 Titer | Standard Deviation 35.833 |
| Compound Exercise of Push-ups | Serologic Response - B/Brisbane/60/2008 | Followup (between 21-28 days, visit 3) | 41.02 Titer | Standard Deviation 39.199 |
Secondary
Serologic Response - B/Phuket/3073/2013
Baseline lab specimen (visit 1, day 0, before immunization) and repeated between 21-28 days (visit 3) after immunization to measure serologic response
Time frame: Day 0 and between 21-28 days (2 points)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ibuprofen | Serologic Response - B/Phuket/3073/2013 | Baseline (day 0, visit 1) | 36.69 Titer | Standard Deviation 44.586 |
| Ibuprofen | Serologic Response - B/Phuket/3073/2013 | Followup (between 21-28 days, visit 3) | 44.78 Titer | Standard Deviation 43.773 |
| Placebo | Serologic Response - B/Phuket/3073/2013 | Baseline (day 0, visit 1) | 40.16 Titer | Standard Deviation 60.321 |
| Placebo | Serologic Response - B/Phuket/3073/2013 | Followup (between 21-28 days, visit 3) | 47.34 Titer | Standard Deviation 58.976 |
| Compound Exercise of Push-ups | Serologic Response - B/Phuket/3073/2013 | Baseline (day 0, visit 1) | 32.89 Titer | Standard Deviation 33.857 |
| Compound Exercise of Push-ups | Serologic Response - B/Phuket/3073/2013 | Followup (between 21-28 days, visit 3) | 49.07 Titer | Standard Deviation 39.578 |
Other Pre-specified
Lactate
A Lactate meter was used to test the exercise group for lactate readings. Two lactate tests was performed for the exercise group at Visit 1, both pre and post Influenza vaccination. The first lactate reading was taken after the blood draw.The second lactate reading was obtained from a fingerstick from the hand opposite to the vaccination arm, ideally within 3-8 minutes after the study subject completes pushups.
Time frame: Immediately prior to Influenza vaccine and 3-8 minutes after Influenza vaccine was administered and after push-ups were completed.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ibuprofen | Lactate | Lactate before pushups | 1.51 mmol/L |
| Ibuprofen | Lactate | Lactate after pushups | 7.69 mmol/L |