Clinical trial NCT05095311
Conditions: Exercise-induced Arterial Hypoxemia
Sponsor: Indiana University
Start date: 2021-05-19; Completion date: 2022-04-27
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Exercise-induced arterial hypoxemia (EIAH), a reduced amount of oxygen in the arterial blood during exercise, has been observed in otherwise healthy, highly-trained endurance athletes during exercise at sea level. The extent of the arterial deoxygenation may be influenced by a histamine-mediated inflammatory response at the pulmonary capillary-alveolar membrane limiting oxygen diffusion. Moreover, while EIAH has been routinely explored in running and cycling, swimming is understudied despite potential mechanistic avenues which may put swimmers at further risk for EIAH. The purpose of this study is threefold: 1) to determine whether highly-trained swimmers experience EIAH during submaximal and maximal exercise, 2) to determine the extent to which histamine release influences oxyhemoglobin saturation during swimming exercise, and 3) to determine whether cetirizine HCl (CH), an H1-receptor competitive inhibitor, can improve oxyhemoglobin saturation during submaximal and maximal swimming exercise. Twenty-four (12 men, 12 women) highly-trained swimmers will complete an intense swimming protocol to assess the histamine response to intense exercise. A subset with the highest histamine responses will participate in three additional sessions (placebo, NS, and CH conditions) which will include a swimming aerobic capacity test and 5-minutes of swimming at both 70 and 85% of their maximal oxygen uptake.

Detailed description:
For the first testing session, participants will report to the Indiana University Human Performance Laboratory to complete a medical screening and, if willing, consent to the procedures of the study. The medical screening will include measurements of height, weight, resting heart rate, resting blood pressure, and resting pulmonary function along with a health history questionnaire.

The second testing session consists of an assessment of risk factors for development of EIAH, specifically changes in blood biomarkers pre- and post-swimming exercise. Participants will report to the Counsilman-Billingsley Aquatics Center and complete an exercise protocol designed to elicit an inflammatory response. Venous blood draws will be performed to assess participants' pre-exercise complete blood count and pre- and post-intense exercise concentrations of plasma IL-1β, IL-8, plasma histamine, whole blood histamine, and histamine release. Measurements of hemoglobin concentration and hematocrit will also be performed pre- and post-exercise in order to correct biomarker concentrations for fluid loss during exercise. Swimmers of each sex that exhibit the largest histamine release will be selected for further study until at least four swimmers of each sex complete all three experimental trials.

Twelve swimmers (n = 6 men, n = 6 women) will be selected for further trials. Those selected for further study will visit the Human Performance Laboratory on two occasions separated by at least 48 hours and no more than 60 days. Apart from receiving a placebo (PL) or drug treatment (cetirizine HCl, CH) prior to exercise, participants will perform identical protocols on each visit to the laboratory. Participants will report to the lab and consume either a placebo or CH pill, followed by a health history update questionnaire and their resting pulmonary function will be measured. Participants will then complete a self-selected warm-up that will be standardized across all testing sessions, followed by instrumentation. The exercise protocol beings with a progressive swimming test to maximum aerobic capacity (V̇O2max) in a swimming flume, followed by two constant load work bouts at approximately 70 and 85% of the previously recorded HRmax while peripheral capillary oxyhemoglobin saturation (SpO2) is continuously monitored. Participants will receive a 20-min break between each work bout. Drug treatments will be assigned in a double-blind, randomized crossover fashion such that each participant receives each treatment. Concentrations of plasma histamine, whole blood histamine, and histamine release will be assessed from pre- and post-exercise blood samples.

Arms: arm 1: This subset of 12 individuals will complete all experimental study visits, and will ingest either 1) a placebo pill and placebo inhaler contents or 2) a cetirizine HCl pill (10 mg) and placebo inhaler contents in a randomized order and double-blind fashion. arm 2: Twenty-four total individuals will be recruited for the initial portion of the study, and the aforementioned 12 (6 men, 6 women) will be a subset of the initial 24. The other 12 participants will not take part in further study.
Interventions: intervention 1: Cetirizine HCl intervention 2: Placebo
Intervention descriptions: intervention 1: Eight participants will be administered 10 mg of cetirizine HCl to examine whether this drug can improve their oxyhemoglobin saturation during exercise. intervention 2: The placebo pill is a sugar-free gelatin pill casing. The placebo inhaler contains isotonic saline.

Protocol documents:
Prot_SAP_000.pdf: 
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The effect of cetirizine HCl on exercise-induced 
arterial hypoxemia in highly-trained swimmers 
 
Robert F. Chapman, PhD, FACSM 
Department of Kinesiology 
Indiana University - Bloomington 
 
Co-Investigator 
 
Curtis Goss, MS 
Department of Kinesiology 
Indiana University - Bloomington 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Support Provided by: 
General research funds (Chapman) 
University Graduate School Doctoral Research Grant 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents: 
 
1.0 
Background & Rationale 
2.0 
Objective(s) 
2.1 
Primary Objective 
2.2 
Secondary Objective 
3.0 
Outcome Measures 
3.1 
Primary Outcome Measures 
3.2 
Secondary Outcome Measures 
4.0 
Eligibility Criteria 
4.1 
Inclusion Criteria 
4.2 
Exclusion Criteria 
5.0 
Study Design 
6.0 
Enrollment/Randomization 
7.0 
Study Procedures 
8.0 
Study Calendar 
9.0 
Reportable Events 
10.0 Data Safety Monitoring 
11.0 Study Withdrawal/Discontinuation 
12.0 Statistical Considerations 
13.0 Data Management 
14.0 Privacy/Confidentiality Issues 
15.0 Follow-up and Record Retention 
16.0 References 
17.0 Appendix 
17.1 Payment Schedule 
17.2 Attachments 
 
 


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1.0 
Background & Rationale 
 
A constant supply of oxygen is critical for the maintenance of oxygen uptake (V̇ O2) 
during exercise and increasing volumes of oxygen are needed to accommodate increases 
in exercise intensity.  In healthy humans during exercise, the oxygen-carrying molecule 
hemoglobin is almost fully (>94%) saturated with oxygen, and a difference between the 
oxygen tension in the alveoli of the lung and the arterial blood exists (20-25 mmHg) but 
does not necessarily compromise V̇ O2.  However, a subset of otherwise healthy, highly-
trained endurance athletes demonstrate a phenomenon termed exercise-induced arterial 
hypoxemia (EIAH), which refers to a decline in arterial oxyhemoglobin saturation (<92%) 
during exercise at sea level and is marked by a widened alveolar-arterial oxygen 
difference (25-40 mmHg) (Dempsey and Wagner, 1999).  Over the past half-century, this 
phenomenon has been well-chronicled in highly-trained and elite athletes across 
numerous sporting disciplines, especially running (Chapman and Stager, 2008; Dempsey 
et al., 1984; Gavin and Stager, 1999; Harms and Stager, 1995) and cycling (Derchak et 
al., 2000; Rice et al., 1999; Tanner et al., 2013). 
 
There are four recognized mechanisms for the development of EIAH: inadequate 
compensatory hyperpnea, diffusion limitation, alveolar ventilation-perfusion (V̇ A/Q̇ ) 
mismatch, and pulmonary veno-arterial shunt (West and Luks, 2016).  EIAH is of concern 
to athletes because oxyhemoglobin saturation is associated with oxygen transport and, 
by extension, V̇ O2MAX (Dempsey and Wagner, 1999).  Many researchers have 
investigated the relative contributions of inadequate compensatory hyperpnea, V̇ A/Q̇  
mismatch, and veno-arterial shunt to the development of EIAH; however, the contribution 
of a diffusion limitation has not been as thoroughly examined, despite the fact a diffusion 
limitation is a viable mechanism by which athletes may ultimately experience EIAH 
(Prefaut et al., 2000). 
 
There are two theorized routes by which a diffusion limitation could occur during 
exercise and ultimately lead to EIAH.  One mechanism is that EIAH can develop due to 
an inflammatory response secondary to injury at the interface of the alveoli and pulmonary 
capillaries (West and Mathieu-Costello, 1995).  Numerous studies (Groves et al., 1987; 
Reeves et al., 1990; Wagner et al., 1986; West and Mathieu-Costello, 1999) have 
estimated that pulmonary capillary pressure rises high enough to cause injury at the very 
thin (2-3 µm) diffusive barrier, which has been observed in rabbits, dogs, and 
Thoroughbred racehorses (Birks et al., 1994; Tsukimoto et al., 1991; West et al., 1991).  
The other mechanism by which a diffusion limitation could occur is through a subclinical 
pulmonary edema, where fluid from the capillaries leaks into the alveolar space (Hodges 
et al., 2006).  Each of these mechanisms would cause a widening off the diffusive barrier 
through inflammation following injury or through a thickening of the aqueous barrier 
between the air in the lung and the blood, respectively, and are not necessarily mutually 
exclusive and could occur in the same individual. 
 
Histamine is a compound that has been implicated in adding to the diffusion 
limitation associated with EIAH (Prefaut et al., 1997; Prefaut et al., 2000). Exercise 
(especially intense exercise) is a well-documented initiator of acute-phase inflammatory 
processes, including stimulating the action of granulocytic cells (Camus et al., 1993; 


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Suzuki et al., 2002). Indeed, various compounds that appear in greater concentrations in 
the blood of athletes who experience EIAH have been implicated in signaling and 
modulating histamine release from its progenitor cells (Horio et al., 2010; Mucci et al., 
2000, 2001; Prefaut et al., 2000; Suzuki et al., 2002). Once released from basophils 
(blood-derived) and mast cells (tissue-derived), histamine is available to bind to the large 
quantity of H1-receptors available in the pulmonary circuit (Panula et al., 2015). The 
binding of histamine to pulmonary H1-receptors causes microvascular permeability 
edema and tissue inflammation characteristic of several pathological conditions (Borriello 
et al., 2017; Brigham and Owen, 1975; Probst et al., 1978) which, even at subclinical 
levels not nearly considered anaphylaxis, would ostensibly impair gas exchange during 
exercise. Furthermore, compounds that inhibit the release of histamine from mast cells 
(Coyle and Stager, 2001; Prefaut et al., 1997) and competitively inhibit histamine (Coyle 
and Stager, 2001) have been shown to attenuate EIAH in athletes. 
 
Nearly all of the studies involving EIAH mechanisms and athletes have used either 
running or cycling as the mode of exercise.  However, competitive swimming is an 
interesting, yet understudied, athletic arena in which to examine EIAH.  There is limited 
evidence (Holmer et al., 1974; Labreche, 2012; Spanoudaki et al., 2004) to suggest that 
competitive swimmers might experience EIAH.  However, it is difficult to draw definitive 
conclusions from these studies, as they likely either did not have an adequate subject 
population (Holmer et al., 1974) or did not utilize an exercise protocol with sufficient 
intensity or duration (Labreche, 2012; Spanoudaki et al., 2004) in which to determine the 
presence of EIAH.  There are numerous plausible mechanisms by which EIAH could 
develop in swimmers, especially those that are highly-trained.  First, swimming occurs 1) 
in water, with 2) a horizontal body position, and both of these conditions cause an 
increase in venous return of blood to the heart which would theoretically increase 
pulmonary capillary pressure (Pendergast et al., 2015).  Second, swimmers breathe at 
incredibly high flow rates (Leahy et al., 2019) with their lungs almost completely inflated 
(Li, 2016), both of which serve to increase pulmonary capillary pressure (Fu et al., 1992).  
Third, breathing in competitive swimming is “phase-locked,” meaning swimmers can only 
breathe when their face is out of the water “in-phase” with their swimming stroke, and this 
ultimately leads to a relative hypoventilation compared to land exercise (Li, 2016).  Finally, 
there is myriad literature linking swimming and pulmonary edema, and this phenomenon 
is well-chronicled in swimmers of many ages and abilities (Adir et al., 2004; Hohmann et 
al., 2018). 
 
Therefore, the goals of the present study are twofold: 
 
1. To examine whether EIAH occurs in highly-trained swimmers, and 
2. To examine histamine release as a mechanism by which EIAH occurs in 
highly-trained athletes. 
 
 
Objective(s) 
2.1 
Primary Objective 
 
Aim 1. To confirm whether that highly-trained swimmers experience EIAH 


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It is hypothesized that highly-trained swimmers will experience EIAH, as 
evidenced by a decrement in peripheral capillary oxyhemoglobin saturation 
(SpO2) of 5% or greater from rest to submaximal and/or maximal exercise. 
 
Aim 2. To test whether a pharmacological agent that is a competitive 
inhibitor to histamine (cetirizine HCl) can improve nadir SpO2 during 
submaximal (70 and/or 85% V̇ O2max) and/or maximal (100% V̇ O2max) 
exercise. 
 
It is hypothesized that the pharmacological agents will significantly (p < 
0.05) increase nadir SpO2 during all exercise intensities. This will be 
assessed using a linear mixed model including random effects for subject, 
subject within-treatment, and subject within-intensity to account for the 
repeated measures design.  Treatments (placebo and cetirizine HCl), 
intensity (70, 85, and 100% of V̇ O2max), and the interaction between 
treatment and intensity will be included. Main effects and interactions will 
be tested using F-tests from a two-way ANOVA. 
 
 
2.2 
Secondary Objective 
 
Aim 3. To test whether degree of desaturation from rest to maximal exercise 
(∆SpO2,rest-SpO2,100%) is correlated with the magnitude of histamine release 
from rest to maximal exercise (∆%Hrest-%H100%).   
 
It is hypothesized that degree of saturation and histamine release will be 
significantly (p < 0.05) correlated. Correlational strength will be assessed 
via Pearson correlation coefficient. 
 
 
 
3.0 
Outcome Measures/Endpoints 
3.1 
Primary Outcome Measures 
Plasma histamine, whole blood histamine, histamine release, peripheral 
capillary oxyhemoglobin saturation, oxygen consumption (V̇ O2) 
 
3.2 
Secondary Outcome Measures 
Basophil count, IL-1β, IL-8, exercise ventilation (V̇ E), tidal volume (VT), 
breathing frequency (fB), carbon dioxide production (V̇ CO2) 
 
 
4.0 
Eligibility Criteria 
4.1 
Inclusion Criteria 
• 
Men and women  
• 
18-35 years old 
• 
Current collegiate or professional swimmer 
• 
Currently training at least 300 minutes per week 
• 
Self-reported to be healthy 


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4.2 
Exclusion Criteria 
• 
Not within defined age range 
• 
Current diagnosis of or using medication for: 
o Severe allergies 
o Asthma 
o Exercise-induced asthma 
o Exercise-induced bronchoconstriction 
• 
Pulmonary function test considered to be abnormal (defined as forced 
vital capacity (FVC) <80% of predicted, forced expiratory volume in one 
second (FEV1) <80% predicted, and/or FEV1/FVC ratio >5% of the 
predicted ratio) 
• 
Hypertension during screening (systolic blood pressure >139 or 
diastolic blood pressure >89) 
• 
Current tobacco or electronic cigarette use or consistent use within the 
last 2 years 
• 
A contraindication for use of cetirizine HCl: 
o Previous adverse reaction to cetirizine HCl or a similar 
medication 
o Allergy to the food additives E218 or E216 
o An intolerance to or inability to absorb some sugars, such as 
lactose or sorbitol 
o Liver or kidney failure 
o Epilepsy or similar condition 
o A condition that makes urinating difficult 
o Use of midodrine or ritonavir 
• 
Are pregnant or could possibly be pregnant by self-report 
• 
Subjects with current, irregular menstrual cycles (amenorrhea) or who 
had irregular menstruation patterns for greater than one year 
• 
People who answer ‘yes’ to any of the pre-participation screening 
questions on page one of the PAR-Q+ questionnaire.  
 
 
 


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5.0 
Study Design 
 
 
 
 
Figure 1: Experimental design for proposed study protocol. 
 
The general study protocol is outlined in Figure 1.  For the first testing session, 
participants will report to the Indiana University Human Performance Laboratory to 
complete a medical screening and, if willing, consent to the procedures of the study.  The 
medical screening will include measurements of height, weight, resting heart rate, resting 
blood pressure, and resting pulmonary function along with a health history questionnaire. 
The second testing session consists of an assessment of risk factors for development of 
EIAH, specifically changes in blood biomarkers pre- and post-swimming exercise.  
Participants will report to the Counsilman-Billingsley Aquatics Center and complete an 
exercise protocol designed to elicit an inflammatory response.  Venous blood draws will 
be performed to assess participants’ pre-exercise complete blood count and pre- and 
post-intense exercise concentrations of plasma IL-1β, IL-8, plasma histamine, whole 
blood histamine, and histamine release.  Measurements of hemoglobin concentration and 
hematocrit will also be performed pre- and post-exercise in order to correct biomarker 


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concentrations for fluid loss during exercise.  Twelve swimmers (n = 6 men, n = 6 women) 
will be selected for further trials.   
 
Those selected for further study will visit the Human Performance Laboratory on 
two occasions separated by at least 48 hours and no more than 60 days.  Apart from 
receiving a placebo (PL) or drug treatment (cetirizine HCl, CH) prior to exercise, 
participants will perform identical protocols on each visit to the laboratory.  Participants 
will report to the lab and consume either a placebo or CH pill, followed by a health history 
update questionnaire and their resting pulmonary function will be measured.  Participants 
will then complete a self-selected warm-up that will be standardized across all testing 
sessions, followed by instrumentation. The exercise protocol beings with a progressive 
swimming test to maximum aerobic capacity (V̇ O2max) in a swimming flume, followed by 
two constant load work bouts at approximately 70 and 85% of the previously recorded 
HRmax while peripheral capillary oxyhemoglobin saturation (SpO2) is continuously 
monitored.  Participants will receive a 20-min break between each work bout.  Drug 
treatments will be assigned in a double-blind, randomized crossover fashion such that 
each participant receives each treatment.  Concentrations of plasma histamine, whole 
blood histamine, and histamine release will be assessed from pre- and post-exercise 
blood samples. 
 
6.0 
Enrollment/Randomization 
We plan to recruit up to 30 participants for this project to ensure that at least 24 
participants will complete the first two visits of the study. 
 
Participants will be recruited from the Indiana University varsity swim team and the 
associated professional training group.  Indiana University is home to a NCAA Division I 
swim team that is perennially among the nation’s top-10 for both men and women. 
Participants will be recruited from this group of over 50 swimmers using a standard email 
script.    
 
Potential participants will be given the basic information about the study and schedule an 
appointment for screening if they indicate that they would be interested in participating. 
Participants will be provided a with detailed description of study procedures prior to study 
enrollment. Participants will be asked to read the consent form at this time and be 
encouraged to ask any questions. Participants can then: 1) sign the consent form; 2) take 
it home for further consideration; or 3) decide not to participate. Participants will be 
screened once written informed consent has been given. 
 
Experimental trials 3 and 4 will be completed in a double-blinded randomized crossover 
design.  The randomization order will be determined using a customized program (Excel; 
Microsoft Corporation, Redmond, WA, USA).  Subjects will be randomized using the 
randomization list by order of enrollment in the study by a researcher listed on the IRB 
personnel.  This researcher will also be responsible for drug administration but will 
otherwise not participate in any data collection or analyses. 
 
 
 


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7.0 
Study Procedures 
All of the below mentioned procedures are being conducted for purposes of the research. 
Please see Table 1 for information regarding which visit to the laboratory these 
procedures will take place. 
 
• Facilities: Visit 2 will take place at the Counsilman-Billingsley Aquatics Center, a 
44,651 square foot aquatics center used by Indiana's varsity swimming and diving 
programs. It contains an eight-lane Olympic-sized pool spanning 30,512 square feet 
with depth ranging from seven to eight feet to allow for greater speed. A photo 
depicting the Counsilman-Billingsley Aquatics Center is below (Figure 3). 
 
 
 
Figure 2: Photo of the Counsilman-Billingsley Aquatics Center where Visit 2 will 
take place. 
 
 
Visits 3 and 4 will take place in the swim flume (Endless Pool). This pool works like a 
“swimming treadmill,” pushing water from the front (near side in Figure 4) to the back at 
various flow rates to simulate various swimming speeds. A standard pulley is affixed to 
the back of the flume to add a tethered load to the swimmer, like changing the “grade” on 
a treadmill. This is a familiar training environment for high-level competitive swimmers. A 
photo depicting the swim flume in the IUB School of Public Health is below (Figure 4). 
 


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Figure 3: Photo of the swim flume where Visits 3 and 4 will take place. 
 
 
• Height: Body height will be measured using a stadiometer. 
 
• Weight: Weight will be measured using a scale.  
 
• Heart rate: Resting heart rate will be obtained by taking a radial pulse for 15 seconds 
during the screening procedure. Exercising and pre-exercise heart rate will be 
continuously recorded using a specialized waterproof swimming heart rate monitor 
(Cardio Swim HR monitor; Freelap, Switzerland).  
 
• Urine specific gravity: Urine specific gravity will be measured via refractometry. 
 
• Blood pressure: Blood pressure will be measured using standard brachial artery 
manual auscultation techniques. 
 
• Health history questionnaire: Participants will complete a health history questionnaire 
to ensure they meet the inclusion and exclusion criteria. 
 


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• Health history update questionnaire: Upon each visit to the laboratory participants will 
complete the heath history update questionnaire to ensure no changes in their health 
history has occurred. 
 
• Pulmonary function: Pulmonary function will be examined using procedures described 
by the American Thoracic Society. Following 10 min seated rest, participants will be 
fitted with a previously disinfected non-rebreathing mouthpiece. Following 30 s of 
normal breathing the participants will be instructed to take a maximal inhalation 
followed by a maximal forced exhalation. This very large, very fast breath will be 
repeated three times. From this test peak expiratory flow rate (PEFR), forced vital 
capacity (FVC), forced expiratory volume in one second (FEV1), and the maximal 
expiratory flow at 50% vital capacity (MEF50) will be measured. These tests will be 
used to determine if the participants classify as having normal pulmonary function 
(Barreiro and Perillo, 2004). 
 
• Venous blood sample: Venous blood will be drawn by a trained researcher from an 
antecubital vein using standard aseptic techniques, as defined by the World Health 
Organization. Each blood draw will be ~10 mL (Experimental Trials) or 15 mL 
(Selection Exercise Protocol) total. Measurements include: 
 
o Complete blood count: Samples will be collected into EDTA-coated 
Vacutainer tubes (Becton Dickinson, Franklin Lakes, NJ). The samples will 
be immediately stored on ice and transported to a local medical facility 
(Student Health Center, Indiana University, Bloomington, Indiana) that will 
perform a complete blood count using an automated hematology analyzer 
(SX-1000i; Sysmex, Kobe, Hyogo, Japan).  The complete blood count will 
assess hemoglobin, hematocrit, white blood cell count, red blood cell count, 
mean corpuscular volume, mean corpuscular hemoglobin concentration, 
platelets, neutrophil percentage, lymphocyte percentage, monocyte 
percentage, eosinophil percentage, basophil percentage, neutrophil 
number, lymphocyte number, monocyte number, eosinophil number, 
basophil number, red cell distribution width standard deviation, red cell 
distribution width coefficient of variation, and mean platelet volume. 
 
o Plasma volume correction: In order to account for loss of plasma volume 
during exercise, all plasma-derived post-exercise measures will be 
corrected via the methods of Dill and Costill (1974).  First, post-exercise 
blood volume (BVA) is determined via the equation: 
 
𝐵𝐵𝐵𝐵𝐴𝐴= 𝐵𝐵𝐵𝐵𝐵𝐵× 𝐻𝐻𝐻𝐻𝐵𝐵
𝐻𝐻𝐻𝐻𝐴𝐴
 
 
where HbB is the pre-exercise hemoglobin concentration, BVB is the pre-
exercise blood volume and is 100 for the purpose of this equation, HbA is 
the post-exercise hemoglobin concentration.  Whole blood histamine 
concentration will then be corrected based on the differences in the blood 


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volume pre- and post-exercise (ΔBVA-BVB%).  BVA is then used to 
determine post-exercise red cell volume (CVA) via the equation: 
 
𝐶𝐶𝐶𝐶𝐴𝐴= 𝐵𝐵𝐵𝐵𝐴𝐴× 𝐻𝐻𝐻𝐻𝐻𝐻𝐴𝐴 
 
where HctA is the post-exercise hematocrit value.  CVA is then used to 
determined post-exercise plasma volume (PVA) via the equation: 
 
𝑃𝑃𝑃𝑃𝐴𝐴= 𝐵𝐵𝐵𝐵𝐴𝐴−𝐶𝐶𝐶𝐶𝐴𝐴 
 
Concentration of plasma-derived biomarkers will then be corrected based 
on the differences in plasma volume pre- and post-exercise (ΔPVA-PVB%).  
Hemoglobin and hematocrit will be assessed in triplicate from a venous 
blood sample. 
 
o Plasma IL-1β: Samples will be collected into EDTA-coated Vacutainer tubes 
(Becton Dickinson, Franklin Lakes, NJ). The samples will be immediately 
stored on ice and transported to the laboratory where they will be 
centrifuged at 4°C at 1,300 g for 10 minutes and 2000 g for 15 minutes 
(model X-22R; Beckman, St. Louis, MO).  Two-hundred microliters of 
plasma will be aliquoted into 0.5 mL cryogenic storage vials (CryoKING®, 
Biologix, Jinan, Shandong, China) and stored immediately at −80°C.  
Samples will be later diluted accordingly and analyzed in duplicate using a 
commercially-available enzyme-linked immunoassay (ELISA) kit (Invitrogen 
#BMS224HS; Thermo Fisher Scientific, Waltham, MA, USA) with detection 
by spectrophotometry (Powerwave XS™ Spectrophotometer, Bio-Tek 
Instruments, Winooski, VT).  Based on a previous study, it is expected that 
plasma IL-1β in this cohort will be 1-15 pg·mL-1 (Mucci et al., 2000).  The 
sensitivity of this assay is 0.05 pg·mL-1 and the range is 0.16-10.0 pg·mL-1. 
 
o Plasma IL-8: Samples will be collected, processed, and stored as previous.  
Samples will be later analyzed in duplicate with a commercially-available 
ELISA kit (Invitrogen #KHC0084; Thermo Fisher Scientific, Waltham, MA, 
USA) with detection as previous.  Based on a previous study, it is expected 
that plasma IL-8 will be 0-10 pg·mL-1 (Mucci et al., 2000).  The sensitivity of 
this assay is <100 fg·mL-1 and the range is 0.39-25 pg·mL-1. 
 
o Plasma histamine: Samples will be collected as previous.  The samples will 
be immediately stored on ice and transported to the laboratory where they 
will be centrifuged at 4°C at 900 g for 15 minutes (model X-22R; Beckman, 
St. Louis, MO).  Samples will be analyzed in duplicate with a commercially-
available ELISA kit (AB213975; Abcam, Cambridge, United Kingdom) with 
detection as previous.  Based on a previous study, it is expected that 
plasma histamine will be 1-6 ng·mL-1 (Mucci et al., 2000).  The sensitivity of 
this assay is 0.03 ng·mL-1 and the range is 0.098-25 ng·mL-1. 
 


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o Whole blood histamine: Samples will be collected into heparinized 
Vacutainer tubes (Becton Dickinson, Franklin Lakes, NJ).   Fifty microliters 
of whole blood will be pipetted into 950 µL of distilled water and stored at 
−80°C in 1 mL vials (Eppendorf Tubes®; Eppendorf, Hamburg, Germany) 
until analysis.  The diluted blood will be fully thawed and frozen twice more 
to ensure cell lysis.  For analysis, thawed samples will be centrifuged as 
previous and the supernatant will be analyzed using a commercially-
available ELISA kit and detected as previous.  Based on a previous study, 
it is expected that whole blood histamine will be between 600-1400 ng·mL-
1 (Mucci et al., 2000).  The sensitivity of this assay is 0.03 ng·mL-1 and the 
range is 0.098-25 ng·mL-1. 
 
o Histamine release: Histamine release (%H) will be calculated via the 
equation: 
%𝐻𝐻= 𝑃𝑃𝑃𝑃
𝑊𝑊𝑊𝑊× 100 
 
where PH is the plasma histamine concentration and WH is the whole blood 
histamine concentration. 
 
• Selection exercise test: This test will take place in a standard 25-yard swimming pool 
(Counsilman-Billingsley Aquatics Center).  Following a standardized 1000 yds (914.4 
m) warm-up, an intense exercise protocol will be used to elicit release of inflammatory 
markers.  At his or her fastest sustainable pace, each swimmer will complete 6 x 100 
yards (91.4 meters), 6 x 50 yds (45.7 meters), and 6 x 25 yards (22.9 meters) of 
freestyle swimming with 10 seconds of rest between each of the 18 total bouts.  This 
is a common exercise paradigm that is typically completed by collegiate and 
professional swimmers during their training season. Blood draws for assessment of 
inflammatory markers will be completed 1 hour prior to commencement of the warm-
up and immediately following completion of the last intense exercise bout. 
 
• Peripheral capillary oxyhemoglobin saturation (SpO2): This measurement will take 
place during the experimental trials in the swimming flume in the IU Human 
Performance Laboratory.  A pulse oximetry sensor (Covidien/Medtronic, Dublin, 
Ireland) will be placed on the subject’s forehead after application of a topical 
vasodilator (Finalgon; Boehringer Ingelheim, Ingelheim am Rhein, Germany).  Though 
the probe has its own adhesive, an adhesive bandage patch (Tegaderm; 3M, Saint 
Paul, MN) will be placed over the top to further secure and waterproof the probe below 
a standard swimming cap.  SPO2 will be monitored through a standard bedside pulse 
oximetry unit (Nellcor N600x; Covidien/Medtronic, Dublin, Ireland) outputting an 
analog signal to a customized A/D board (Hector Engineering, Ellettsville, IN) and 
recorded at a 1 Hz sampling frequency by a customized computer program (DasyLab 
13.0; Measurement Computing Corporation, Norton, MA).  
 
• Indirect calorimetry: During the experimental trials in the swimming flume, resting and 
exercise metabolic (V̇ O2 and V̇ CO2) and ventilatory (V̇ E, fB, and VT) variables will be 


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measured breath-by-breath using a portable metabolic computer (K5; Cosmed, 
Rome, Italy) suspended above the Endless Pool and adapted for swimming exercise 
(Aquatrainer, Cosmed, Rome, Italy).  This portable system has been determined to be 
valid and reliable while using breath-by-breath mode (Guidetti et al., 2018) and will be 
calibrated according to the manufacturer’s instructions prior to each test.  The 
swimmer will breathe through a customized two-way, nonrebreathing snorkel 
mouthpiece (Hans Rudolph, Shawnee, KS). 
 
• Graded exercise test: After a self-determined warm-up and a rest period of at least 2 
minutes, a progressive maximal exercise test will be performed in a specially 
constructed, customized variable water flow pool (Endless Pools, Aston, PA, USA), 
with subjects swimming against a flow rate of approximately 1.5 m·s-1 for men and 
1.31 m·s-1 for women tethered to a pulley with a 1.2 and 1 kg mass, respectively.  After 
two minutes, the tethered mass will be increased by 0.2 kg every two minutes until 
each subject reaches volitional exhaustion.  Metabolic and ventilatory variables and 
SPO2 will be measured as described below.  Subjects’ heart rates during the tests will 
be continuously recorded (Cardio Swim HR Monitor; Freelap, Switzerland).  V̇ O2MAX 
will be considered as the maximal value attained during the test, provided at least two 
of three criteria are met, which will include an RER of greater than 1.05, achievement 
of 90% of age-predicted maximal heart rate, and an increase in V̇ O2 of less than 0.15 
L/min over the previous workload.  Plasma histamine, whole blood histamine, and 
histamine release will be measured before and after this test as previous. 
 
• Constant load tests: Following the maximum exercise test, subjects will perform 
constant load swimming exercise at approximately 70 and 85% of subjects’ previously 
recorded HRMAX during that session.  The tethered mass used to elicit the workloads 
will be estimated during the first 20-minute rest period by performing a linear 
regression between HR and tethered mass to approximate the tethered mass that 
would elicit 70 and 85% of maximum HR.  Subjects will swim for 5 minutes.  Metabolic 
and ventilatory variables and SPO2 will be measured as described below.  Plasma 
histamine, whole blood histamine, and histamine release will be measured following 
these tests as previous. 
 
• Drug administration - An opaque sugar-free gelatin capsule (Capsuline, Dania Beach, 
Florida, USA) will be administered 60 minutes prior to testing and will either be empty 
(placebo) or contain CH (10 mg; Zyrtec®; Johnson & Johnson, New Brunswick, NJ, 
USA) according to the visit condition. 
 
 
Timeline of procedures: 
• Screening Visit (Visit 1): Once participants arrive at the laboratory, an investigator will 
obtain written informed consent after all procedures and study risks are fully explained 
and all questions answered. Participants will then complete a pre-exercise health 
screening questionnaire and a health history questionnaire. The PI and/or approved 
study team member will administer these questionnaires/assessments. These 
individuals can fully explain any technical terms and answer any inquiries related to 


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the questionnaires. Participants will also have their resting heart rate and blood 
pressure, height, and weight in a private room. They will then complete a pulmonary 
function test. This visit will take approximately 1 h.  If the participant is female, they 
will be asked to self-identify when their last menses (period) occurred.  To prevent sex 
differences caused by fluctuations in hormone across the menstrual cycle, 
experimental visits (2-5) for female participants will only be tested during the first 7 
days following menstruation when estrogen and progesterone hormones are at their 
lowest levels. 
 
• Selection Exercise Protocol (Visit 2): Participants will arrive to the Counsilman-
Billingsley Aquatics Center after abstaining from allergy medication for 48 hours, 
intense exercise for 24 hours, caffeine and alcohol for 12 hours, and food for 2 hours. 
They will complete the health history update questionnaire to ensure there have been 
no changes in their health history. Following a standardized 1000 yds (914.4 m) warm-
up, an intense exercise protocol will be used to elicit release of inflammatory markers.  
At his or her fastest sustainable pace, each swimmer will complete 6 x 100 yards (91.4 
meters), 6 x 50 yds (45.7 meters), and 6 x 25 yards (22.9 meters) of freestyle 
swimming with 10 seconds of rest between each of the 18 total bouts.  A venous blood 
draw will be completed 30 minutes prior to commencement of the warm-up and 
immediately following completion of the last intense exercise bout. 
 
• Experimental Trials (visits 3 and 4): Prior to all testing sessions, participants will be 
asked to abstain from allergy medication for 48 hours, intense exercise for 24 hours, 
caffeine and alcohol for 12 hours, and food for 2 hours.  Prior to the sessions 3-4, 
participants will also be asked to consume a similar diet the night before and day of 
each testing session.  Women participants will be asked to self-identify when their last 
menses occurred.  In order to prevent sex differences caused by fluctuations in 
hormone across the menstrual cycle, women participants will only be tested during 
the first 7 days following menstruation (when estrogen and progesterone hormones 
are at their lowest levels) for sessions 2-4 (Allen et al., 2016).  Apart from receiving a 
placebo (PL) or drug treatment (CH) prior to exercise, participants will perform 
identical protocols on each visit to the laboratory.  Participants will report to the lab 
and consume either a placebo or CH pill, followed by a health history update 
questionnaire and their resting pulmonary function will be measured.  Participants will 
then complete a self-selected warm-up that will be standardized across the two testing 
sessions, followed by instrumentation. The exercise protocol beings with a 
progressive swimming test to maximum aerobic capacity (V̇ O2max) in a swimming 
flume, followed by two constant load work bouts at approximately 70 and 85% of the 
previously recorded HRmax while peripheral capillary oxyhemoglobin saturation (SpO2) 
is continuously monitored.  Participants will receive a 20-min break between each 
work bout.  Drug treatments will be assigned in a double-blind, randomized crossover 
fashion such that each participant receives each treatment.  Concentrations of plasma 
histamine, whole blood histamine, and histamine release will be assessed from a 
venous blood draw one hour prior to commencement of the aerobic capacity test, and 
immediately following the aerobic capacity test and each of the two constant load 
bouts. 


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8.0 
Study Calendar 
The following procedures will be undertaken during the visits. 


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Table 1: Description of Study Procedures that will take place on each visit to the laboratory. 
STUDY PROCEDURES 
Screening 
(Visit 1) 
Selection 
Exercise Test 
(Visit 2) 
Experimental Trials – 
Randomized Crossover 
(Visits 3-4) 
Placebo 
Cetirizine HCl 
Height 
X 
 
X 
X 
Weight 
X 
 
X 
X 
Heart rate 
X 
 
X 
X 
Urine specific gravity 
 
X 
X 
X 
Blood pressure 
X 
 
 
 
Health history questionnaire 
X 
 
 
 
Health history update questionnaire 
 
X 
X 
X 
Pulmonary function 
X 
 
X 
X 
Complete blood count 
 
X 
 
 
Plasma IL-1β 
 
X 
 
 
Plasma IL-8 
 
X 
 
 
Plasma histamine 
 
X 
X 
X 
Whole blood histamine 
 
X 
X 
X 
Histamine release 
 
X 
X 
X 
Selection exercise test 
 
X 
 
 
Peripheral capillary oxyhemoglobin saturation 
 
 
X 
X 
Indirect calorimetry 
 
 
X 
X 
Graded exercise test 
 
 
X 
X 
Constant load tests 
 
 
X 
X 
Placebo pill 
 
 
X 
 
Cetirizine HCl pill 
 
 
 
X 


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9.0 
Reportable Events 
 
Safety will be constantly monitored during all data collection activities. This will occur on 
a participant-by-participant basis. If a suspected adverse event occurs, the principal 
investigator will immediately report to the IRB and cooperate with the IRB in any 
necessary investigation. All safety data will also be reviewed in weekly lab meetings, 
particularly as it relates to changes to the risk-benefit ratio.  
 
If any of the following adverse events, which are specific to the procedures conducted in 
this study, were to occur, they will be reported within 5 business days to the IRB using 
standard operating procedures. 
• Infection at venous blood draw site 
• Loss of consciousness or fainting 
• Adverse drug reaction 
• Loss of confidentiality 
• Injury requiring hospitalization 
• Death 
 
Other events deemed as events occurring outside the criteria above will be reported to 
the IU IRB reported within 5 business days using standard operating procedures. If any 
event occurs that would potentially impair the health of the subject, the experiment will be 
halted, and the IRB will be notified. 
 
Any incident, experience, or outcome that meets all the following criteria will also be 
reported:  
(1) unexpected (in terms of nature, severity, or frequency) given  
a. the research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and informed 
consent document; and  
b. the characteristics of the subject population being studied;  
(2) related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and  
(3) suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
Subjects will be informed of possible risks before consenting to participate through the 
informed consent document. Details of risks and discomforts for the procedures, and 
steps taken to lessen the probability and/or magnitude of these risks are noted below.  
 
• Bacterial/Viral Transmission: There is a risk of germ transmission through shared face 
masks, despite cleaning and treatment in an anti-bacterial solution following each use. 
Researchers will thoroughly scrub all shared equipment with anti-bacterial detergent 
and warm water immediately following use. 


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• Exercise: Submaximal (low and moderate effort) and maximal (all-out effort) exercise 
tests of healthy individuals, as described by the American College of Sports Medicine, 
present little risk and do not require medical clearance for individuals under the age 
of 40.  Potential risks and/or discomforts can include episodes of temporary light-
headedness, chest discomfort, leg cramps, occasional irregular heartbeats, and 
abnormal blood pressure responses.  The risk of heart attack, although minor, 
(approximately 1 to 2 in 10,000) does exist.  One death occurs for roughly every 
880,000 man hours of submaximal exercise in apparently healthy individuals. 
 
• Drowning: There is a risk of drowning during swimming exercise.  All participants have 
undergone many years of swimming training.  During the Selection Exercise Protocol, 
lifeguards from Campus Recreational Sports will be present.  During the Experimental 
Trials, swimmers will be closely monitored by researchers, at least one of whom has 
completed safety training in accordance with USA Swimming coaching standard. 
 
• Drug administration: 
 
o Cetirizine HCl: Serious side effects of cetirizine HCl ingestion are 
exceedingly rare, and in very rare cases subjects can experience 
anaphylaxis. Cetirizine HCl can have adverse reactions with midodrine (low 
blood pressure medication), ritonavir (an HIV treatment), and could 
exacerbate symptoms of any medication that can cause drowsiness, dry 
mouth, or infrequent urination. Mild side effects of cetirizine HCl include 
drowsiness, headaches, dry mouth, nausea, dizziness, stomach pain, 
diarrhea, sore throat, cold-like symptoms of the nose, itching, paresthesia 
in the hands or feet, and feeling agitated. We have previously used cetirizine 
HCl in the following projects in our lab: 
 
o IRB #1706871260: The Individual Exercise Performance Response to 
Altitude: Implication for the Warfighter (PI: Chapman; Publication in 
progress) 
 
In order to help further mitigate the risk of drug administration, a board-certified 
physician, Dr. Andrew K. Watters, MD, will acquire the pharmaceuticals for the project 
and will instruct researchers on best practice for drug administration. He will not 
oversee any other aspects of the study.  
 
• Venous blood sample: Participants will likely experience discomfort during venous 
blood draws and in rare circumstances may feel lightheaded or faint. This risk will be 
minimized by the venipuncture always occurring in the semi-recumbent or supine 
position. There is a rare risk of infection following venous blood draws. This risk will 
be minimized by blood draws only being conducted by trained laboratory personnel. 
 
• Loss of confidentiality: There is a potential risk for loss of confidentiality. This risk will 
be alleviated by only using de-identified information. 


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• Electricity and Water: There is a risk of operating electrical equipment in proximity to 
water.  All equipment that is connected to an electrical outlet will never be suspended 
above the pool and will be secured with safety straps in a fashion that will not allow 
their entry into the pool.  The Cosmed K5 is battery-powered and will be the only 
device suspended above the water (during Experimental Trials only).  The device will 
be connected by multiple metal components to a steel guide wire connected to a steel 
frame over the pool (see Figure 3). 
 
• Other risks: There may be other risks that we cannot predict. 
 
10.0 Data Safety Monitoring 
 
The primary investigator is responsible for the data and safety monitoring. In addition, Dr. 
Zac Schlader, a faculty member within the Department of Kinesiology, will serve as an 
independent data safety monitor for the study. Data quality, subject recruitment, accrual, 
retention, outcome and adverse event data will be monitored on a weekly basis.  
 
Data will be monitored by subject number. Thus, analysis of data will be performed without 
any identifying features to individuals. Statistical software will be used to analyze data for 
significance. Results will be reported through traditional scientific outlets such as peer-
reviewed manuscript and presentations at national and international meetings. 
Communication with the IRB regarding safety will be reported directly by the principal 
investigator.  
 
11.0 Study Withdrawal/Discontinuation 
 
Subjects can voluntarily withdraw from the study at any time by contacting any of the 
researchers on the study via any available means (personal contact, email, phone, etc.). 
If a researcher on the project wishes to withdraw a subject from the study, they will contact 
the subject directly (personal contact, phone, email, etc.). Possible indications for 
withdrawal by a researcher include a change in their health history that excludes them 
from participation and an inability to keep appointments or follow or understand the rules 
of the protocol. Data collected up to the time of withdraw (either voluntary or by the study 
team) may be used for analysis.  
 
12.0 Statistical Considerations 
 
Sample size justification was conducted using data from a study with a similar design 
(Coyle and Stager, 2001) which compared the effect of diphenhydramine HCl (a 
competitive inhibitor to histamine similar to CH) to a placebo on SaO2ear in male cross-
country runners running at 70, 80, 90, and 100% of V̇ O2max.  A depiction of the study’s 
data can be found in Table 2 below. 
 
 
 
 


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Table 2: SaO2ear data from Coyle, 2001 
 
Intensity (% V̇ O2max) 
Treatment 
70 
80 
90 
100 
Placebo 
93.7 ± 0.7% 
93.4 ± 2.5% 
93.0 ± 2.5% 
89.8 ± 3.1% 
Diphenhydramine HCl 
96.5 ± 1.2% 
96.2 ± 1.0% 
95.8 ± 1.2% 
94.2 ± 1.8% 
 
A two-way (treatment x intensity) ANOVA using these data produced a Cohen’s f of 1.22 
for the treatment main effect.  Therefore, it was determined that using an a priori α value 
of 0.05, an estimated twelve subjects are necessary to achieve a power of 0.80.  The 
sample size calculation was conducted using G*Power 3.1.9.7 (ANOVA: Fixed effects, 
special, main effects and interactions).  Due to the randomized crossover design, all 
twelve subjects (n = 6 men, n = 6 women) will complete all experimental treatments (PL 
and CH) at all intensities (70, 85, and 100% of V̇ O2max). 
 
Previous investigations (Anselme et al., 1994; Mucci et al., 2001) have observed a strong, 
positive, and significant (r > 0.7; p < 0.05) correlation between ∆%H (V̇ O2max - rest) and 
∆PaO2 (rest - V̇ O2max).  Using a regression equation (∆%H = 0.0444(∆PaO2) - 0.1137; r = 
0.80) from Anselme and colleagues (1994), a conservative estimate that a ∆PaO2 > 10 
mmHg represents EIAH (Prefaut et al., 2000), we intend to recruit participants for the 
experimental trials who experience a ∆%H > 0.33 during the Selection Exercise Protocol.  
However, should this inclusion criterion not be met by at least eight subjects, those 
experiencing the highest ∆%H during the Selection Exercise Protocol will be recruited 
instead. 
 
For proof of principle that EIAH can be prospectively identified using ∆%H, a small control 
group (n=2 men, n=2 women) will also be recruited.  For this group, we intend to recruit 
participants who exhibit the lowest ∆%H during the Selection Exercise Protocol.  These 
participants will  complete both conditions of the experimental trials. 
 
Insufficient data exist to establish a prevalence rate of EIAH among endurance athletes.  
Attempts have been made to establish prevalence rates in cyclists (Powers et al., 1988) 
and runners (Constantini et al., 2017), however no such data exist for swimmers.  
Estimates of prevalence rates range from approximately 70% (Constantini et al., 2017) in 
highly-trained endurance runners to 32% (Coneys et al., 2011) in untrained individuals. 
As prevalence rates of EIAH have been demonstrated to increase with aerobic training 
status (Dominelli and Sheel, 2019), it is likely that the true prevalence of EIAH in highly-
trained swimmers is between these values. Therefore, to ensure enrollment of an 
adequate number of swimmers who experience EIAH, a prevalence estimate of 50% will 
be utilized. Using a binomial distribution and a target of 8 EIAH-afflicted highly-trained 
swimmers, recruiting 26 swimmers (n = 13 men, n = 13 women) for the Selection Exercise 
Protocol provides a >95% probability that the population will contain at least 8 EIAH-
afflicted highly-trained swimmers. In order to account for potential participant withdrawal, 
we anticipate recruiting no more than 30 individuals. 


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Prior to conducting statistical analysis all data will be visually inspected for normality and 
potential outliers using kernel density and quantile-quantile plots.  Summary statistics of 
the mean, standard deviation, median, and range will be calculated for all variables of 
interest.   
 
Hypothesis 1. EIAH has been previously defined by a decrement in SpO2 of ≥ 5%. Should 
a participant experience this during submaximal or maximal exercise, the hypothesis will 
be confirmed. 
 
Hypothesis 2. Prior to analyses, any carry-over effect will be identified using a two-way 
linear mixed model (visit order x time), independent of the drug treatment (placebo,  or 
cetirizine HCl).  If a carry-over effect is observed, a regressor for visit order group will be 
included in all subsequent analyses. 
In order to test for potential differences in the dependent variables of interest, linear mixed 
models will be used including random effects for subject, subject within-treatment, and 
subject within-intensity to account for the repeated measures design.  Treatment (PL and 
CH), intensity (70, 85, and 100% of V̇ O2max) and the interaction between treatment and 
intensity will be included.  Main effects and interactions will be tested using F-tests from 
a two-way ANOVA.  Statistical significance will be assessed using a pre-determined α 
level of 0.05.  Where significant main effects or interactions are observed, estimated 
marginal means will be used to test for differences in the drug conditions and adjusted for 
multiple comparisons using Dunnett’s method. 
 
Hypothesis 3. The correlation between the change in histamine release (Δ%Hpre-%Hpost) 
and the change in SPO2 at V̇ O2max (ΔSPO2rest-SPO2@100%) will be assessed in the pooled 
experimental and control cohorts (n=12) by a Pearson correlation coefficient using a pre-
determined α level of 0.05. 
 
13.0 Statistical Data Management 
 
Primary data will be collected via direct data capture from measurement instruments and 
stored electronically on an electronic spreadsheet on a password protected computer.  
The storage location will be backed up manually every week.  Quality assurance steps 
will be confirmed by plotting the data prior to formal analyses. Outliers will be identified 
and checked for authenticity in the database and other original data documents. 
Extraction and cleaning of data that will be used for analysis will be carried out after each 
block of subjects used in the randomization of visits 3, 4, and 5 have completed all 
laboratory visits.   
14.0 Privacy/Confidentiality Issues 
 
Informed consent will be obtained, and the testing procedures will be completed in a 
closed, private laboratory setting at the School of Public Health (SPH), with only the 
participant and investigators present.  
 


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Aside from the Screening Exercise Protocol, all testing will take place in a closed, private 
laboratory setting in the School of Public Health.  All participants will be assigned an 
identification number, which will then be used when recording and analyzing data. A code 
list containing the participants names and identification numbers will be stored separately 
in a locked filing cabinet and will only be available to the investigators. The reports 
generated as a result of this investigation will not identify individual subjects. Data will be 
collected and stored on password protected computers located in the Human 
Performance Laboratories, which are always kept locked. Any paper data will be stored 
in a locked filing cabinet inside a locked office. Primary data are backed up by manual 
download to an encrypted flash drive once per week, which is then stored in a separate 
locked office in a locked filing cabinet accessible only to the investigators.  Access to all 
data from this study will be strictly limited to the investigators which will be listed on the 
personnel section of the IRB.  This includes the PI, graduate student investigators, and 
laboratory technicians who have all completed the appropriate training to handle this type 
of data.   
 
While testing is in progress, a sign will be outside the laboratory door to prevent people 
not associated with the study from entering. 
 
15.0 Follow-up and Record Retention 
 
We anticipate that all participants will be enrolled within 36 months. Any identifiable data 
(e.g., signed consent forms) will be maintained for a minimum of 3 years. De-identified 
data will be stored indefinitely. Only investigators will have full access to data. All 
electronic data will be kept on password protected computers, while paper data will 
remain in locked file cabinets. 
 
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Allen, A.M., McRae-Clark, A.L., Carlson, S., Saladin, M.E., Gray, K.M., Wetherington, 
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Li, T. (2016). Ventilatory strategies of competitive swimmers performing maximal and 
submaximal swimming and cycling exercise (Beijing, China: Beijing Sport University). 
Mucci, P., Durand, F., Lebel, B., Bousquet, J., and Prefaut, C. (2000). Interleukins 1-
beta, -8, and histamine increases in highly trained, exercising athletes. Med Sci Sports 
Exerc 32, 1094-1100. 
Mucci, P., Durand, F., Lebel, B., Bousquet, J., and Prefaut, C. (2001). Basophils and 
exercise-induced hypoxemia in extreme athletes. J Appl Physiol 90, 989-996. 
Panula, P., Chazot, P.L., Cowart, M., Gutzmer, R., Leurs, R., Liu, W.L.S., Stark, H., 
Thurmond, R.L., and Haas, H.L. (2015). International Union of Basic and Clinical 
Pharmacology. XCVIII. Histamine receptors. Pharmacol Rev 67, 601-655. 


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Pendergast, D.R., Moon, R.E., Krasney, J.J., Held, H.E., and Zamparo, P. (2015). 
Human physiology in an aquatic environment. Compr Physiol 5, 1705-1750. 
Powers, S.K., Dodd, S., Lawler, J., Landry, G., Kirtley, M., McKnight, T., and Grinton, S. 
(1988). Incidence of exercise induced hypoxemia in elite endurance athletes at sea 
level. Eur J Appl Physiol 58, 298-302. 
Prefaut, C., Anselme-Poujol, F., and Caillaud, C. (1997). Inhibition of histamine release 
by nedocromil sodium reduces exercise-induced hypoxemia in master athletes. Med Sci 
Sports Exerc 29, 10-16. 
Prefaut, C., Durand, F., Mucci, P., and Caillaud, C. (2000). Exercise-induced arterial 
hypoxaemia in athletes. Sports Medicine 30, 47-61. 
Probst, K., Millen, J.E., and Glauser, F.L. (1978). The effects of endogenous and 
exogenous histamine on pulmonary alveolar membrane permeability. Am J Respir Crit 
Care Med 117, 1063-1068. 
Reeves, J.T., Groves, B.M., Cymerman, A., Sutton, J.R., Wagner, P.D., Turkevich, D., 
and Houston, C.S. (1990). Operation Everest II: cardiac filling pressures during cycle 
exercise at sea level. Respir Physiol 80, 147-154. 
Rice, A.J., Thornton, A.T., Gore, C.J., Scroop, G.C., Greville, H.W., Wagner, H., D., 
W.P., and Hopkins, S.R. (1999). Pulmonary gas exchange during exercise in highly 
trained cyclists with arterial hypoxemia. J Appl Physiol 87, 1802-1812. 
Spanoudaki, S.S., Maridaki, M.D., Myrianthefs, P.M., and Baltopoulos, P.J. (2004). 
Exercise induced arterial hypoxemia in swimmers. J Sports Med Phys Fitness 44, 3442-
3348. 
Suzuki, K., Nakaji, S., Yamada, M., Totsuka, M., Sato, K., and Sugawara, K. (2002). 
Systemic inflammatory response to exhaustive exercise: cytokine kinetics. Exerc 
Immunol Rev 8, 6-48. 
Tanner, D.A., Duke, J.W., and Stager, J.M. (2013). Ventilatory patterns differ between 
maximal running and cycling. Respir Physiol Neurobi 191, 9-16. 
Tsukimoto, K., Mathieu-Costello, O., Prediletto, R., Elliott, A.R., and West, J.B. (1991). 
Ultrastructural appearances of pulmonary capillaries at high transmural pressures. J 
Appl Physiol 71, 573-582. 
Wagner, P.D., Gale, G.E., Moon, R.E., Torre-Bueno, J.R., Stolp, B.W., and Saltzman, 
H.A. (1986). Pulmonary gas exchange in humans exercising at sea level and simulated 
altitude. J Appl Physiol 61, 260-270. 
West, J.B., and Luks, A.M. (2016). West's respiratory physiology: the essentials, Tenth 
edn (New York: Wolters Kluwer). 


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West, J.B., and Mathieu-Costello, O. (1995). Stress failure of pulmonary capillaries as a 
limiting factor for maximal exercise. Eur J Appl Physiol 70, 99-108. 
West, J.B., and Mathieu-Costello, O. (1999). Structure, strength, failure, and remodeling 
of the pulmonary blood-gas barrier. Annu Rev Physiol 61, 543-572. 
West, J.B., Tsukimoto, K., Mathieu-Costello, O., and Prediletto, R. (1991). Stress failure 
in pulmonary capillaries. J Appl Physiol 70, 1731-1742. 
 
17.0 Appendix 
17.1 Payment schedule 
 
Participants will be compensated with $100 for completing the Selection Exercise 
Protocol (n=26).  Participants selected for the experimental trials (n=12) will 
receive $100 for each trial (Visits 3 and 4) completed, for a total of $300.  
Compensation will be paid by VISA gift card. 
  
17.2 Attachments 
 
The following Questionnaires have been included as attachments: 
- 
Heath History Questionnaire 
- 
Health History Update Questionnaire 
 
 
 

ICF_003.pdf: 
 
  
Protocol #10766 v03.16.2022  
  
  
  
  
  
          Page 1 of 10  
INDIANA UNIVERSITY INFORMED CONSENT STATEMENT FOR RESEARCH  
  
The Effect of Cetirizine HCl on Exercise-Induced Arterial Hypoxemia in Highly-Trained Swimmers 
  
ABOUT THIS RESEARCH   
You are being asked to participate in a research study.  Scientists do research to answer important 
questions which might help change or improve the way we do things in the future.   
  
This consent form will give you information about the study to help you decide whether you want to 
participate.  Please read this form, and ask any questions you have, before agreeing to be in the study.  
  
TAKING PART IN THIS STUDY IS VOLUNTARY  
You may choose not to take part in the study or may choose to leave the study at any time.  Deciding 
not to participate, or deciding to leave the study later, will not result in any penalty or loss of benefits 
to which you are entitled, and will not affect your relationship with the Indiana University (IU) 
Bloomington, School of Public Health Bloomington, your athletic team, or the Human Performance 
Laboratories. 
  
WHY IS THIS STUDY BEING DONE?  
Oxygen is vital to maintaining endurance exercise performance. Some otherwise healthy individuals 
experience a decrease in the amount of oxygen in their blood while exercising, a phenomenon called 
exercise-induced arterial hypoxemia (EIAH). EIAH is marked by a widening difference between the 
pressure of oxygen in the lung compared to the blood and, though it has been studied for nearly 50 
years, little is known about why it occurs. What is currently understood is that the type of exercise, 
aerobic fitness, and sex may influence whether a given individual experiences EIAH. The inflammatory 
effects of histamine (a molecule that signals inflammation) could explain why EIAH occurs in some 
individuals, as its effects in the lung would cause symptoms associated with EIAH.  Previous studies 
have shown that drugs that stop the action of histamine can alleviate EIAH.  Furthermore, while EIAH 
has been studied extensively in a variety of athletes, few data exist examining EIAH in swimmers, 
creating a knowledge gap in understanding a group of athletes whose response to exercise and 
chemically treated exercise environment (a chlorinated pool) is unique among exercise modes. 
  
You were selected as a possible participant because you are a highly-trained swimmer. The study is 
being conducted by Dr. Robert Chapman Department of Kinesiology (Indiana University, School of 
Public Health – Bloomington).    
  
HOW MANY PEOPLE WILL TAKE PART?  
If you agree to participate, you will be one of 30 participants taking part in this research.  
  
WHAT WILL HAPPEN DURING THE STUDY?  
If you agree to be in the study, you will do the following things:  
  


 
  
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• 
You will be asked to visit the Human Performance Laboratories for Visit 1.  These laboratories 
are located at the IU School of Public Health Building at 1025 E. 7th Street, Bloomington, IN 
47405. Parking is free (with a pass obtained from the researcher) in gated parking area outside 
of building near the Woodlawn field and tennis courts. 
• 
You will be asked to visit the Counsilman-Billingsley Aquatics Center for Visit 2. This facility is 
located at the Student Recreational Sports Center at 1601 Law Lane, Bloomington, IN 47408. 
Parking is free in the gated parking area on Law Lane (validated inside at the Counsilman-
Billingsley Aquatics Center). 
• 
Should you qualify for the Experimental Trials, you will be invited to visit the Human 
Performance Laboratories on 2 more occasions (Visits 3 and 4).  During these visits, you will 
either be administered placebos (pills that cause no physiological effects) or cetirizine HCL 
(brand name: Zyrtec; an allergy medication). You will not be told (blinded) whether you are 
taking cetirizine HCL or placebo for each of the visits. 
• 
For Visits 3 and 4 there will be a minimum of 5 days and a maximum of 60 days between trials.  
• 
For female subjects, Visits 2 through 4 (if applicable) will be scheduled to take place during the 
first 7 days following menstruation.   
  
This is a brief description of what will happen on each study visit.  There are further details below this 
section explaining each study procedure as well as the risks associated with that procedure.  
  
Screening visit (Visit 1):   
• 
Once you arrive at the Human Performance Laboratory, an investigator will obtain written 
informed consent after all procedures and study risks are fully explained and all questions 
answered.   
• 
You will then complete a pre-exercise health screening questionnaire (PAR-Q+) and a health 
history questionnaire that will assess your readiness for exercise and whether you have any 
medical conditions indicating a potential adverse reaction to any of the study procedures. 
• 
You will then have your heart rate, blood pressure, height, and weight measured in a private 
room. You will then complete a pulmonary function test, where you will breathe through a tube 
so we can measure lung volumes and lung function.  
• 
If you are determined to be ineligible for the study during this visit, you will not be allowed to 
participate in this study. If you are determined to be ineligible during screening, we will not use 
your data. 
• 
This visit will take approximately 2 hours. 
 
Selection exercise protocol (Visit 2):   
• 
If you are a female, Visit 2 will be scheduled during the first 7 days of your menstrual cycle. 
• 
You will be asked to report to the Counsilman-Billingsley Aquatics Center well hydrated and 
after abstaining from allergy medication for 48 hours, intense exercise for 24 hours, caffeine 
and alcohol for 12 hours, and food for 2 hours.   
• 
Upon arrival at the laboratory, you will complete a health history update questionnaire to 
ensure no relevant changes in your health history have occurred. In the event of any changes to 


 
  
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          Page 3 of 10  
your health history, you will be removed from the study if you meet any of the exclusion 
criteria. 
• 
A small sample of urine will be used to determine if you are well hydrated prior to participating. 
If you are a female, the same small sample of urine will be used to confirm a negative a 
pregnancy test. 
• 
A 3-teaspoon blood sample will then be taken. 
• 
After a waiting period, you will begin a 1000-yard warm-up swim prescribed by the researchers. 
• 
You will then complete 6x100-yard swims, 6x50-yard swims, and 6x25-yard swims as quickly as 
possible with 10 seconds rest between each bout (Selection Exercise Test). 
• 
You will then immediately exit the pool and a 3-teaspoon blood sample will be taken. You will 
then be free to leave the pool area. 
• 
This visit will take approximately 1.5 hours. 
  
Experimental trials (Visits 3 and 4, if applicable):   
• 
Prior to Visit 3, the drug treatment conditions (placebo or cetirizine HCl) will be randomly 
assigned to Visits 3-4. However, you will be blinded by the research team from what condition 
you are being given during each of the experimental trials. 
• 
If you are a female, Visits 3-4 will be scheduled during the first 7 days of your menstrual cycle. 
• 
You will be asked to report to the Human Performance Laboratory well hydrated and after 
abstaining from allergy medication for 48 hours, intense exercise for 24 hours, caffeine and 
alcohol for 12 hours, and food for 2 hours.   
• 
Upon arrival at the laboratory, you will complete a health history update questionnaire to 
ensure no relevant changes in your health history have occurred. In the event of any changes to 
your health history, you will be removed from the study if you meet any of the exclusion 
criteria. 
• 
You will then receive the pill drug treatment corresponding to the visit number. The pill 
treatments are: 
o Placebo – sugar-free gelatin capsule 
o Cetirizine HCl – cetirizine HCl pill (Zyrtec®) encased in a sugar-free gelatin capsule 
• 
A small sample of urine will be used to determine if you are well hydrated prior to participating. 
If you are a female, the same small sample of urine will be used to confirm a negative a 
pregnancy test. 
• 
A 2-teaspoon blood sample will then be taken. You will then complete a pulmonary function 
test, where you will breathe through a tube so we can measure lung volumes and lung function. 
• 
You will then complete a warm-up in the swimming flume consisting of up to 10 minutes of 
swimming at the first stage of the aerobic capacity test. Men will swim against a flow rate of 
approximately 1.5 meters per second (m/s) and a pulley mass of 1.2 kilograms (kg). Women will 
swim against a flow rate of approximately 1.31 m/s and a pulley mass of 1 kg. 
• 
At the end of the warm-up, you will exit the swimming flume and fully dry off. Researchers will 
apply a small amount of a vasodilator cream (Finalgon®) to your forehead and, after a period of 
approximately 10 minutes, you will then be instrumented (fitted) with a device that will 
monitor your blood oxygen levels. 


 
  
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• 
You will then be instrumented with a device that will measure your energy expenditure. You 
will breathe in the water through a snorkel-like mouthpiece while wearing a nose clip. 
• 
You will then complete a Graded Exercise Test to exhaustion in the swimming flume. You will 
begin this test swimming against the same flow rate and pulley mass as in the warm-up. The 
pulley mass will be increased by 0.2 kg every 1 minute until you cannot continue swimming. 
• 
A 2-teaspoon blood sample will then be taken, and you will begin your first 20-minute rest 
period. 
• 
During the rest period, you will complete a pulmonary function test, where you will breathe 
through a tube so we can measure lung volumes and lung function. 
• 
You will then be similarly instrumented and swim at the same flow rate and a pulley mass 
corresponding with 70% of your maximal heart rate (the fastest rate at which your heart can 
beat) for 5 minutes (Constant Load Test). 
• 
A 2-teaspoon blood sample will then be taken, and you will begin your second 20-minute rest 
period. 
• 
You will then be similarly instrumented and swim at the same flow rate and a pulley mass 
corresponding with 85% of your maximal heart rate for 5 minutes (Constant Load Test). 
• 
A 2-teaspoon blood sample will then be taken. Following this blood draw, all measurement 
devices will be removed, and you will be free to leave the lab.    
• 
This visit will take approximately 2.5 hours. 
  
Experimental Procedures: The procedures listed below are designed for research and are not for 
medical purposes.  
 
Blood sample:  
Description: A small volume of blood will be drawn from a vein in your arm. At each blood draw 2-3 
teaspoons of blood will be obtained.  If you only complete the Selection Exercise Protocol, we will collect 
a total of 6 teaspoons of blood. If you are selected for the Experimental Trials, we will collect a total of 
22 teaspoons of blood. If it is not possible to obtain a blood sample from a vein in your arm prior to or 
following exercise a blood sample may be obtained by using a prick to your fingertip.  Hematocrit (the 
percentage of your blood that is composed of red blood cells) and hemoglobin concentrations (how 
much of the oxygen-binding molecule hemoglobin is in your blood) will also be tested.  These blood 
samples may be stored indefinitely.  
Potential Risks: You may experience discomfort and in rare circumstances you may feel lightheaded or 
faint. There is also a rare risk of infection. Having trained individuals draw your blood using clean 
techniques will minimize this risk.  
Duration: Visits 2, 3, and 4. There will be 2 blood draws during Visit 2, and 4 blood draws in Visits 3-4 (if 
applicable). Approximately 30 seconds in duration.  
 
Heart rate:  
Description: Heart rate will be measured by fitting a waterproof brassiere-like harness with two 
electrodes.  
Potential Risks: None. 
Duration: Visits 3 and 4, measured continually.  


 
  
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Blood pressure:  
Description: Your blood pressure will be monitored using a cuff placed on your upper arm that is 
inflated and deflated periodically.  
Potential Risks: You may feel slightly uncomfortable due to inflation of the cuff around your arm or 
fingertip.  
Duration: Visit 1, measured once. 
  
Blood oxygen levels:    
Description: How much oxygen is in your blood will be measure using a light-based sensor placed on 
your forehead.  
Potential Risks: None.  
Duration: Visits 3 and 4, measured continually.  
  
Energy expenditure:    
Description: The air you breathe out will be analyzed by a computer.   
Potential Risks: None.  
Duration: Visits 3 and 4, measured continually.  
 
Lung function:  
Description: Following 10 minutes seated rest, you will be asked to breathe on a mouthpiece. Following 
30 seconds of normal breathing you will be instructed to breathe in as far as possible and to breathe out 
as fast as possible. A computer will analyze the volume of air that you breathed in and out. This will be 
repeated three times.   
Potential Risks: None.  
Duration: Visit 1. This measurement will take approximately 20 minutes.  
  
Body weight:  
Description: You will be asked to measure your body weight on a scale in a private room. 
Potential Risks: None.  
Duration: Visit 1.  
  
Body height:  
Description: Your body height will be measured using a stadiometer.  
Potential Risks: None.  
Duration: Visit 1.  
 
Questionnaires:    
Description: You will take short surveys to assess your current health and physical activity levels, and 
whether there have been any changes in your health history.  
Potential Risks: None.  
Duration: Visit 1, this measurement will take approximately 15 min. On Visits 2 & 3, this measurement 
will take approximately 3 minutes.  


 
  
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Urine Specific Gravity:  
Description: Your hydration status will be measured use a urine refractometer. 
Potential Risks: None.  
Duration: Visits 2-4.  
 
  
  
Timeline of study procedures:  
Table 1: Description of study procedures that will take place on each visit to the laboratory.  
STUDY PROCEDURES 
Screening 
(Visit 1) 
Selection Exercise 
Test (Visit 2) 
Experimental Trials – 
Randomized Crossover 
(Visits 3-4) 
Placebo 
Cetirizine HCl 
Height 
X 
 
X 
X 
Weight 
X 
 
X 
X 
Heart rate 
X 
 
X 
X 
Urine specific gravity 
 
X 
X 
X 
Blood pressure 
X 
 
 
 
Health history 
questionnaire 
X 
 
 
 
Health history update 
questionnaire 
 
X 
X 
X 
Lung function 
X 
 
X 
X 
Blood sample 
 
X 
X 
X 
Selection exercise test 
 
X 
 
 
Blood oxygen levels 
 
 
X 
X 
Energy expenditure 
 
 
X 
X 
Graded exercise test 
 
 
X 
X 
Constant load tests 
 
 
X 
X 
Placebo pill 
 
 
X 
 
Cetirizine HCl pill 
 
 
 
X 
 


 
  
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WHAT ARE THE RISKS OF TAKING PART IN THE STUDY?  
Bacterial/Viral Transmission: There is a risk of germ transmission through shared face masks, despite 
cleaning and treatment in an anti-bacterial solution following each use. Researchers will thoroughly 
scrub all shared equipment with anti-bacterial detergent and warm water immediately following use. 
 
Exercise: Submaximal (low and moderate effort) and maximal (all-out effort) exercise tests of healthy 
individuals, as described by the American College of Sports Medicine, present little risk and do not 
require medical clearance for individuals under the age of 40.  Potential risks and/or discomforts can 
include episodes of temporary light-headedness, chest discomfort, leg cramps, occasional irregular 
heartbeats, and abnormal blood pressure responses.  The risk of heart attack, although minor, 
(approximately 1 to 2 in 10,000) does exist.  One death occurs for roughly every 880,000 man hours of 
submaximal exercise in apparently healthy individuals. 
 
Drowning: There is a risk of drowning during swimming exercise.  During the Selection Exercise Protocol, 
lifeguards from Campus Recreational Sports will be present.  During the Experimental Trials, you will be 
closely monitored by researchers, at least one of whom has completed safety training in accordance 
with USA Swimming coaching standard. 
 
Drug administration: 
 
o Cetirizine HCl: Serious side effects of cetirizine HCl ingestion are exceedingly rare, and in very rare 
cases subjects can experience anaphylaxis. Cetirizine HCl can have adverse reactions with midodrine 
(low blood pressure medication), ritonavir (an HIV treatment), and could exacerbate symptoms of 
any medication that can cause drowsiness, dry mouth, or infrequent urination. Mild side effects of 
cetirizine HCl include drowsiness, headaches, dry mouth, nausea, dizziness, stomach pain, diarrhea, 
sore throat, cold-like symptoms of the nose, itching, paresthesia (tingling) in the hands or feet, and 
feeling agitated. 
 
Venous blood sample: You may experience discomfort during venous blood draws and may feel 
lightheaded or faint. This risk will be minimized by the venipuncture always occurring in the semi-
recumbent or supine position. There is a rare risk of infection following venous blood draws. This risk 
will be minimized by blood draws only being conducted by trained laboratory personnel. 
 
Electricity and Water: There is a risk of operating electrical equipment in proximity to water.  All 
equipment that is connected to an electrical outlet will never be suspended above the pool and will be 
secured with safety straps in a fashion that will not allow their entry into the pool.  A battery-powered 
device will be the only device suspended above the water (during Experimental Trials only).  The device 
will be connected by multiple metal components to a steel guide wire connected to a steel frame over 
the pool. 
 
Loss of Confidentiality  
Any time information is collected, there is a potential risk for loss of confidentiality.  Every effort will be 
made to keep your information confidential. However, this cannot be guaranteed.  
   
 


 
  
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Other Risks  
There also may be other side effects that we cannot predict.  
  
WHAT ARE THE POTENTIAL BENEFITS OF TAKING PART IN THE STUDY?  
By completing Visit 2, you will receive information regarding your inflammatory response to intense 
exercise.  By completing Visits 3-4 (if applicable), you will receive information regarding your aerobic 
fitness and your ability to maintain arterial blood oxygenation during exercise.   
  
WILL I RECEIVE MY RESULTS?  
We may learn things about you from the study activities which could be important to your health or to 
your treatment.  If this happens, this information will be provided to you. Some of this information 
relates to your health history, blood pressure, or lung function. You may need to meet with professionals 
with expertise to help you learn more about your research results.  The study team/study will not cover 
the costs of any follow-up consultations or actions. 
  
HOW WILL MY INFORMATION BE PROTECTED?  
Your personal information will remain confidential.  We cannot guarantee absolute confidentiality.  Your 
personal information may be disclosed if required by law.  No information which could identify you will 
be shared in publications about this study. 
  
Organizations that may inspect and/or copy your research records for quality assurance and data 
analysis include groups such as the study investigator and his/her research associates, the Indiana 
University Institutional Review Board or its designees, and any state or federal agencies who may need 
to access your medical and/or research records (as allowed by law). Federal agencies may include the 
Food and Drug Administration (FDA). 
  
WILL MY INFORMATION BE USED FOR RESEARCH IN THE FUTURE?  
Information or specimens collected from you for this study may be used for future research studies or 
shared with other researchers for future research.  If this happens, information which could identify you 
will be removed before any information or specimens are shared.  Since identifying information will be 
removed, we will not ask for your additional consent. 
 
A description of this clinical trial will be available on ClinicalTrials.gov, as required by U.S. law.  This 
website will not include information that can identify you.  At most, the website will include a summary 
of the results.  You can search this website at any time. 
  
Specimens collected from you for this research may be used to develop products which could be sold in 
the future.  The investigator does not plan to share any profits or losses from the sale of those 
products with you.   
 
WHAT WILL YOU DO WITH MY GENETIC INFORMATION? 
We will not use the specimens collected as a part of this study for whole genome sequencing, which 
involves mapping all of your DNA. 
 


 
  
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WILL I BE PAID FOR PARTICIPATION?   
You will be compensated with $100 for completing Visit 2.  If you are selected for the experimental 
trials, you will receive $100 for each trial (Visits 3 and 4) that you complete, for a total of $300.  
Compensation will be paid by VISA gift card. 
 
WILL IT COST ME ANYTHING TO PARTICIPATE?   
There is no cost to you for taking part in this study.  
  
WHO WILL PAY FOR MY TREATMENT IF I AM INJURED?   
In the event of physical injury resulting from your participation in this study, necessary medical treatment 
will be provided to you and billed as part of your medical expenses.  Costs not covered by your health 
care insurer will be your responsibility.  Also, it is your responsibility to determine the extent of your 
health care coverage.  There is no program in place for other monetary compensation for such injuries.  
However, you are not giving up any legal rights or benefits to which you are otherwise entitled.   Because 
you are participating in research that is not conducted at a medical facility, you will be responsible for 
seeking medical care and for the expenses associated with any care received.    
  
WHO SHOULD I CALL WITH QUESTIONS OR PROBLEMS?  
For questions about the study or a research-related injury, contact the researcher, Dr. Robert Chapman, 
at 812-856-2452.  After business hours or in the event of an emergency, please call Dr. Chapman at 812-
340-0691.    
  
For questions about your rights as a research participant, to discuss problems, complaints, or concerns 
about a research study, or to obtain information or to offer input, please contact the IU Human Subjects 
Office at 800-696-2949 or at irb@iu.edu.  
  
CAN I WITHDRAW FROM THE STUDY?  
If you decide to participate in this study, you can change your mind and decide to leave the study at any 
time in the future.  The study team will help you withdraw from the study safely.  If you decide to 
withdraw, please tell Dr. Chapman of your decision.  
  
Your participation may be terminated by the investigator without regard to your consent in the following 
circumstances: your inability to follow direction, if you cannot attend your scheduled appointments, or 
if a change in your health history between any of the visits to the laboratory meet any of the exclusion 
criteria.  
 


 
  
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PARTICIPANT’S CONSENT  
In consideration of all of the above, I give my consent to participate in this research study.  I will be 
given a copy of this informed consent document to keep for my records.  I agree to take part in this 
study.  
  
Participant’s Printed Name:  
  
  
Participant’s Signature: 
Date:  
  
  
Printed Name of Person Obtaining Consent: 
  
  
  
  
Signature of Person Obtaining Consent: 
Date: