Clinical trial NCT02901054
Conditions: Pain
Sponsor: Washington University School of Medicine
Start date: 2016-08-25; Completion date: 2016-11-17
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Serotonergic 5-HT3 receptors in the central nervous system are involved in pain processing after nerve injury. We are interested in learning if 5-HT3 receptor antagonist ondansetron might be an appropriate drug for treating pain after nerve injury (neuropathic pain), by investigating its bio-distribution in the cerebro-spinal fluid, and the genetic variability that may affect that distribution.

Study procedures will include iv ondansetron administration, serial blood draws, cerebrospinal fluid (CSF) sampling, pregnancy testing, and possible ECG.

Detailed description:

Arms: arm 1: 1. A single 4-mL CSF sample per subject.
2. Serial blood sampling at 0 (pre-infusion), 15, 30, 60, 120, and 180 min after ondansetron administration
Interventions: intervention 1: Ondansetron
Intervention descriptions: intervention 1: A single 15-min intravenous infusion of ondansetron

Protocol documents:
Prot_SAP_001.pdf: 
 
Simon Haroutounian, PhD © 
1 
 
RESEARCH PROTOCOL 
 
 
Investigation of cerebrospinal fluid (CSF) pharmacokinetics of 
ondansetron 
 
Simon Haroutounian, PhD 
Assistant Professor 
Division of Clinical and Translational Research 
Department of Anesthesiology 
Washington University School of Medicine  
660 S. Euclid Ave, Campus Box 8054 
Saint Louis, MO, 63110 
Tel: 314-286-1715  
Fax: 314 286-2948 
E-mail: simon.haroutounian@wustl.edu 
 
 
Co-investigators: 
 
Evan Kharasch, MD, PhD 
Russell D. and Mary B. Shelden Professor of Anesthesiology 
Director, Division of Clinical and Translational Research 
Department of Anesthesiology 
Washington University School of Medicine  
Tel: 314-362-8796 
kharasch@wustl.edu  
 
Carl Nielsen, MD 
Professor of Anesthesiology 
Department of Anesthesiology 
Washington University School of Medicine  
E-mail: nielsenc@anest.wustl.edu  
 
Chris C. Lee, MD, PhD 
Associate Professor of Anesthesiology 
Department of Anesthesiology 
Washington University School of Medicine 
E-mail: climd@wustl.edu 
 
 
 
 
 
 
 
 
 
 
Version Date:  October 18, 2016 


 
Simon Haroutounian, PhD © 
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1.  SYNOPSIS 
 
Study Title 
Investigation of cerebrospinal fluid (CSF) pharmacokinetics of 
ondansetron 
 
Brief Title 
CSF PK of ondansetron 
Objective 
To determine human cerebrospinal fluid (CSF) and plasma 
pharmacokinetic parameters of 5HT3R antagonist ondansetron after 
intravenous administration. 
Hypothesis 
Approaches to enhance CNS penetration of ondansetron might be useful 
for obtaining analgesic effect with 5HTfev antagonists in neuropathic 
pain. 
Study Period 
Planned enrollment duration: Approximately 3 months 
Planned study duration: One (4-hour) study day per subject, on the day 
of knee/hip arthroplasty surgery. 
Number of Subjects 15 evaluable subjects having elective hip or knee arthroplasty with 
spinal anesthesiafrom up to 30 consented subjects. 
Study Treatment  
Single intravenous 15-min infusion of 16mg ondansetron. 
Study Design 
Prospective, open-label, pharmacokinetic pilot study.  
Inclusion and 
Exclusion Criteria 
Inclusion criteria: 
1. Age between 18 and 70 years old;  
2. Patients planned to undergo  hip or  knee arthroplasty with spinal 
anesthesia; 
 
3. Ability to provide informed consent 
Exclusion criteria: 
4. Not giving consent to participate in the study; 
5. Patients with history of or current hepatic or renal insufficiency; 
6. Patients with BMI ≥ 33; 
7. Patients with heart failure or active arrhythmias; 
8. Patients with severe systemic disease that is a constant threat to 
life; 
9. Contraindication or allergy to ondansetron; 
10. Pregnancy or lactation. 
11. Prisoners 
Measurements 
Ondansetron CSF and plasma Pharmacokinetics: 
1. A single 4-mL CSF sample per subject. 
2. Serial blood sampling at 0 (pre-infusion), 15, 30, 60, 120, and 
180 min after ondansetron administration. 
Genotyping: A blood sample will be obtained at baseline for 
determining the following single nucleotide polymorphisms (SNPs) as 
confounders of ondansetron PK parameters: 
1. ABCB1 gene (p-Glycoprotein transporter): C3435T, G2677T, T-
129C, G1199A, C1236T.  


 
Simon Haroutounian, PhD © 
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2. In SLC22A1 gene (OCT1 transporter): R61C, C88R, G401S, 
M420del, G456R. 
Statistical 
Methodology 
This is a pilot/feasibility study. Individual plasma concentration-time 
data will be analyzed using non-compartmental methods in Phoenix 
WinNonlin® 6.1, to determine ondansetron PK parameters such as 
volume of distribution (Vd), clearance (CL), maximum plasma 
concentration (Cmax), and the time to reach maximum concentration 
(Tmax). 
A compartmental population-based PK model will be constructed, to 
determine the pharmacokinetic variables of ondansetron in CSF, and 
allow for the estimation of the partition coefficient between the plasma 
and CSF.  
 


 
Simon Haroutounian, PhD © 
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2.  STUDY PROTOCOL  
 
2.1 Background and Significance 
Neuropathic pain [NeuP] affects 7-8% of the adult population and is particularly challenging 
to treat. More than 30% of neuropathic pain patients continue to suffer despite treatment; and there is 
clearly an urgent need for new treatment approaches. However, the translation of findings from 
current neuropathic pain animal models to clinical trials have been extremely disappointing, with 
multiple pre-clinically promising agents failing to show robust clinical effectiveness; suggesting that 
1) additional pharmacodynamic (PD) and pharmacokinetic (PK) factors responsible for effective 
animal-to-human translation need to be considered, and 2) because of a large inter-subject variability 
in pain mechanisms and treatment response, an “all-comers” approach is suboptimal in yielding 
significant leaps forward in the success of treating neuropathic pain. Therefore, addressing possible 
PK and PD translational gaps and investigating genotypic and phenotypic predictors of response can 
improve the translational process and allow more effective drug discovery and individual analgesic 
tailoring in neuropathic pain. 
Serotonergic 5HT3Rs in the central nervous system (CNS) have been identified as a 
promising pharmacological target in neuropathic pain [1, 2]. After peripheral nerve damage the 
character of serotonergic descending modulation changes from inhibitory to facilitatory through 
5HT3Rs in the spinal cord [3, 4]. This finding is supported by studies demonstrating that intrathecal 
(IT) administration of 5HT3R antagonists such as ondansetron alleviates mechanical and thermal 
hypersensitivity in animal nerve injury models [1, 5]. In contrast to IT administration, systemic 
ondansetron does not produce consistent analgesia. However, this is not surprising, considering that 
CNS concentrations of 5HT3R antagonists such as ondansetron highly depend on the expression level 
of P-glycoprotein (Pgp) - an efflux transporter at the capillaries of the blood-brain barrier (BBB) 
which transports xenobiotics out of the CNS to the systemic circulation [6, 7]. 
Clinical trials performed with 5-HT3 antagonists for treating pain have yielded mixed results. 
Two studies with tropisetron in fibromyalgia have yielded somewhat positive results, but had 
methodological shortcomings, and a well-designed tropisetron study in 30 patients with low back 
pain was negative. Two studies with ondansetron in neuropathic pain were overall negative, but in 
one of the studies, pain reduction 2h after ondansetron administration was larger than with placebo 
[8, 9]. In both these studies individual data (personal communication with the authors) indicate that 
certain patients had good analgesic response to intravenous ondansetron, warranting further 
investigation into the individual response profiles. 
We suggest that one of the caveats leading to unsuccessful clinical translation of the 
promising animal data is related to the essential pharmacokinetic criterion that probably determined 
the lack of efficacy of systemic ondansetron in rodents - i.e. inability to achieve effective 
concentration at the site of action. We propose that sufficient exposure of 5HT3R antagonists at their 
site of action in the CNS, as well as the choice of appropriate pain condition are of key importance 
for testing the clinical effectiveness of 5HT3R antagonists in NeuP. Consequently, the goal of the 
project is to establish detailed CNS pharmacokinetic (PK) parameters of ondansetron, to provide 
sound basis for a future study with enhanced CNS penetration of ondansetron in neuropathic pain. 
Two genetic factors shown to affect the pharmacokinetics and the antiemetic efficacy 
ondansetron are 1) polymorphism in the ABCB1 gene expressing P-glycoprotein, a transporter which 
controls the transport of ondansetron to the CNS via the BBB; and 2) polymorphism in the SLC22A1 
gene expressing organic cation transporter-1 (OCT1), a transporter responsible for hepatic uptake of 


 
Simon Haroutounian, PhD © 
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ondansetron. We will collect the genetic data on these polymorphisms to account for inter-subject 
variability in pharmacokinetic parameters of ondansetron. 
 
2.2 Preliminary Data 
None 
 
2.3 Objective 
The primary objective of the study is:  
To test the feasibility of: 
1. Determining human cerebrospinal fluid (CSF) and plasma pharmacokinetics of 5HT3R 
antagonist ondansetron, after intravenous administration. 
2. Determining single nucleotide polymorphisms in transporters involved in hepatic uptake 
(organic cation transporter-1 [OCT1]) and CNS disposition (P-glycoprotein) of ondansetron 
in human subjects. 
 
2.4 Patient Selection 
 
Overall, 15 evaluable subjects planned to undergo hip or knee arthroplasty with spinal anesthesia at 
Washington University / Barnes Jewish Hospital. We anticipate that we will need to consent 
approximately 30 subjects to achieve the enrollment goal. 
 
2.4.1 Inclusion Criteria 
 
Inclusion criteria: 
1. Age between 18 and 70 years old;  
2. Patients having elective  hip or  knee arthroplasty with spinal anesthesia; 
 
3. Ability to provide informed consent 
 
2.4.2 Exclusion Criteria 
Subjects will not be enrolled if any of the following criteria exist: 
 
1. Not giving consent to participate in the study; 
2. Patients with history of or current hepatic or renal insufficiency; 
3. Patients with BMI ≥ 33; 
4. Patients with heart failure or active arrhythmias; 
5. Patients with severe systemic disease that is a constant threat to life; 
6. Contraindication or allergy to ondansetron; 
7. Pregnancy or lactation. 
8. Prisoners 
 
The following ondansetron contraindications will disqualify subjects from participating: 
1. Congenital QT syndrome 
2. QTc interval>450ms 
3. Concomitant therapy with any of the following drugs: 


 
Simon Haroutounian, PhD © 
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 
First 
generation 
antipsychotic 
medications 
Thioridazine, 
Haloperidol, 
Chlorpromazine, and Pimozide 
 
Second generation antipsychotic medications Ziprasidone and Quetiapine 
 
Azole antifungals Ketoconazole and Fluconazole 
 
Antihistamine Terfenadine, 
 
Antidepressants Trazodone, Citalopram, and Bupropion,  
 
Antiarrythmics Propafenone, Flecainide, and Procainamide 
 
Fluoroquinolone antibiotics  Norfloxacin, Ofloxacin, and Ciprofloxacin 
 
Macrolide antibiotics Erythromycin and Azithromycin 
 
Antiretrovirals of Protease inhibitor (e.g. Ritonavir, Saquinavir) or Non-nucleoside 
reverse transcriptase inhibitors (e.g. Efavirenz, Zidovudine) family. 
 
Cisapride  
 
Other potent inhibitors of Cytochromes P450 2D6 or 3A4. 
 
 
 
2.5 Design and Procedures 
 
2.5.1 Study Design and Methodology 
 
The potential subjects will be recruited from the Washington University / Barnes Jewish Hospital 
center for perioperative assessment and planning (CPAP) and the Washington University Orthopedics 
outpatient clinics, before their scheduled visit for elective knee or hip arthroplasty. Subjects may also 
be recruited from BJH Surgery Registration and the preoperative holding area on the day of surgery. 
Subjects who are potential candidates for the study will be provided with written and oral description 
of the study procedures, benefits, and potential risks. They will be given the opportunity to ask 
questions regarding the study. Informed consent will take place at Washington University/Barnes-
Jewish Hospital medical center campus. 
If agreeing to participate in the study, each subject will sign the informed consent document. Each 
subject who qualifies for entry into the study on the basis of inclusion/exclusion criteria and 
completion of informed consent will be assigned the next available patient number. This indicates 
enrollment in the study. In subjects with a history of or suspected renal or hepatic disorder, blood 
tests will be ordered following consent and reviewed prior to study participation for plasma 
creatinine, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and albumin. 
Subjects with moderate or severe renal or hepatic failure will be excluded from the study at the 
discretion of the PI. Subjects with any history of cardiac arrhythmias will undergo 12 lead ECG to 
rule out QTc interval >450ms and will be excluded from the study. 
Patients’ demographic data will be recorded; height and weight will be measured for calculating 
BMI. Subjects who drop out of the study prior to completing the study will be replaced by using the 
next available subject number. 
 
2.5.2 Study Period 
 


 
Simon Haroutounian, PhD © 
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Subjects will be studied in the Department of Anesthesiology of Washington University-Barnes 
Jewish Hospital, prior to and during their scheduled hip or knee arthroplasty surgery. 
An intravenous catheter will be inserted in an arm for drug administration and in the opposite arm for 
obtaining blood samples to evaluate the plasma concentrations of ondansetron. The former will be 
used also for pre/intraoperative fluids and anesthesia drug administration. 
At baseline, a 5ml blood sample will be collected for pharmacokinetics and another 5ml sample for 
genetic analysis. 
Ondansetron will be administered in a 16mg single dose as a 15 min intravenous  infusion. Although 
up to 32mg doses of intravenous ondansetron have been used in clinical trials, 16mg is currently the 
highest FDA-recommended dose for single administration. Two additional 4mg doses of either IV or 
oral ondansetron will be allowed for postoperative nausea and vomiting treatment in the study 
subjects, at the discretion of the treating physicians. 
A single CSF sample of 4ml will be collected immediately after spinal needle insertion and before 
administration of spinal anesthesia. This procedure is routinely performed in the holding area, 
approximately 30 min before the patient enters the operating room (OR) for planned surgical 
procedure with spinal anesthesia. As only one sample of CSF is obtained from each subject, the 
timing of the infusion will be scheduled at approximately 30, 60, or 120 min before planned pre-
surgical spinal needle insertion. This will allow 3 time-points of CSF samples from the aggregate 
study cohort. For determination of the above timing, the patients will be randomized in blocks of 3 
for infusion timing (approximately 5 subjects per block), to allow even distribution of CSF PK 
sample time-points.  
Six 5mLserial venous blood samples will be obtained from all subjects at 0 (pre-treatment), 15, 30, 
60, 120, and 180 min from the beginning of infusion in each patient, regardless of timing for CSF 
sampling. The samples will be put on ice, centrifuged for 10 min at 5000 rpm. Plasma will be 
transferred to two 1.5mL vials and stored at -80°C until analysis by HPLC-MS. 
The CSF ondansetron pharmacokinetic profile will be constructed using population PK approach, 
according to the exact time of CSF sampling. Ondansetron concentration in plasma (expected 40-
120ng/mL) and CSF (expected 3-12ng/ml) will be determined by HPLC-MS-MS analysis [10].  
 
Ondansetron may cause QT interval prolongation in rare cases; therefore, the subjects’ heart rhythm 
will be monitored throughout the infusion and for approximately 30 min after the end of infusion 
using standard 4 lead monitors in the holding area. No changes will be made to the routing 
intraoperative management and hemodynamic physiological monitoring. with the exclusion of the PK 
blood sampling period. 
 
The DNA isolation and genotyping will include analysis of single nucleotide polymorphisms (SNPs) 
in OCT1 and P-glycoprotein transporters. We will genotype for the following five P-glycoprotein 
(ABCB1) SNPs:  C3435T, T-129C, G1199A, C1236T, G2677T [11-14], and for five OCT1 
(SLC22A1) SNPs: R61C, C88R, G401S, M420del, or G456R that have reported to affect 
ondansetron pharmacokinetics or clinical antiemetic effect. The genotyping will be performed at 
Washington University Genome Technology Access Center. The whole blood samples will be 
extracted using the QiIAamp DNA mini Blood kit (QIAGEN). The DNA will be quantified and 
quality controlled using nanodrop and gel readings. The SNPs will be interrogated using Taqman 
probes (Applied Biosystems).  Each SNP will have its own 20μl reaction well with a final 


 
Simon Haroutounian, PhD © 
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concentration of 1X Taqman probe mix, 1X Taqman PCR master mix, and 20-40ng of DNA.  The 
samples will be cycled and analyzed on CFX96 Real-time PCR Detection System (Bio-Rad). The 
collected blood and DNA samples will be de-identified and coded to ensure patient confidentiality 
and HIPPA compliance. 
 
2.5.3 Minimization of Bias 
There will be no specific sex, ethnic or racial background for enrollment. Plasma and CSF 
ondansetron concentration is not affected by subjects’ or investigators’ knowledge of study aims and 
hypothesis. 
 
2.5.4 Observations and Measurements 
 
 
2.5.4.1 Primary Outcome Measures 
Primary outcome:  
Plasma and CSF concentrations of ondansetron, and CSF to plasma concentration ratio. 
 
2.5.4.2 Secondary Outcome Measures 
Secondary outcomes: 
Non-compartmental modeling to determine plasma PK parameters of ondansetron – i.e. volume of 
distribution (Vd), clearance (CL), maximum CSF and plasma concentration (Cmax), and the time to 
reach these maximum concentrations (Tmax).  
Compartmental modeling using population PK approach to determine CSF pharmacokinetic 
parameters of ondansetron. 
 
2.5.4.3 Pharmacokinetic data analysis: 
Individual plasma concentration-time data will be analyzed using non-compartmental methods. The 
following PK parameters will be calculated and compared between subjects with different transporter 
expression level: volume of distribution, systemic clearance, the elimination half-life, and the total 
area under the concentration-time curve. In addition, a compartmental population-based 
pharmacokinetic model will be constructed, which will evaluate inter-subject variability in 
pharmacokinetic parameters. Preliminary assessment of published data indicates that the systemic 
disposition of ondansetron follows two-compartment model with linear elimination following 
intravenous administration in humans.  
The population model will include a “CSF distribution compartment”, which will allow for the 
estimation of the partition coefficient between the plasma and CSF. The effect of transporter 
expression level phenotypes on individual pharmacokinetic parameters will be evaluated using a 
standard covariate analysis. Utilization of population approach will allow for estimation of population 
mean and individual patients parameters. This pharmacokinetic methodology is especially useful for 
analysis of sparse data (i.e., a single CSF sample from each patient). 
 
2.5.5   Sample Size 
 


 
Simon Haroutounian, PhD © 
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We plan to recruit 15 subjects to the current study, and propose additional enrollment of 60-80 
patients to the subsequent study, upon securing sufficient extramural funding 
Typically, 10-15 subjects per study have been used for the assessment of drug pharmacokinetic 
parameters and is sufficient for a pilot study.  
Weekly, more than 30 total hip or knee arthroplasties with spinal anesthesia are performed at our 
institution. This corresponds to approximately 1000 eligible patients a year that may fulfill the 
inclusion criteria.  
 
2.5.6  Study design considerations 
. A large number of patients undergo total joint arthroplasty at our institution, and spinal anesthesia is 
standard care; therefore, it will be possible to recruit patients who meet the inclusion criteria without 
the added risk of spinal needle insertion. Ondansetron is routinely administered in these patients for 
the prophylaxis or treatment of postoperative nausea and vomiting. 
The dose of 16mg ondansetron was chosen, as this is currently the highest recommended dose by 
FDA for a single administration and was shown safe among patients between ages 18-75. Intravenous 
15-minute infusion is chosen over bolus administration to reduce QTc prolongation risks. We did not 
choose lower doses to be able to reliably measure CSF concentrations, as sampling volume is 
typically limited to about 4mL, to reduce the risk of post spinal headache. The timing of CSF 
sampling was based on intravenous ondansetron PK data [17]. 
 
2.5.7 Clinical Procedures and Laboratory Tests 
Due to the risk of QT interval prolongation with high doses of ondansetron, we exclude patients with 
QTc > 450ms, and any concomitant administration of drugs that increase the pro-arrhythmic risk with 
ondansetron. In addition, all subjects will be monitored with ECG for potential arrhythmias. 
However, it should be noted that ondansetron administration is standard of care in these patients. 
Blood hepatic function and renal tests will be performed and evaluated prior to study treatment for 
any subjects with suspected or known kidney and or liver disease. 
 
3.0 Management of Intercurrent Events 
 
3.1 Adverse Experiences 
The investigators will closely monitor subjects for evidence of ondansetron adverse events.  All 
adverse events will be reported and followed until satisfactory resolution.  The description of the 
adverse experience will include the time of onset, duration, severity, etiology, relationship to the 
study drug (none, unlikely, possible, probable, highly probable), and any treatment required. The 
clinicians will manage any postoperative event related to the spinal anesthesia as standard of care. 
 
3.2 Premature Discontinuation 
If a subject withdraws from the study, the subject will be replaced in order to provide the required 
number of evaluable subjects. Subjects will be withdrawn if the investigator decides that 
discontinuation is in the best interest of the subject, or the subject requests withdrawal from the study. 
 
3.3 Potential Risks 
 
3.3.1 Potential risks from ondansetron 


 
Simon Haroutounian, PhD © 
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Ondansetron systemic effects associated with high plasma concentration may cause cardiac 
arrhythmias.  
In addition, subjects may experience diarrhea, constipation, headache, dry mouth, malaise, elevation 
of liver enzymes (incidence of 5% - when administered with chemotherapy to treat nausea and 
vomiting), and injection site reaction. 
 
Rarely reported adverse effects include: 
Hypokalemia, Fever, Anaphylaxis, Seizures, Temporary blindness. 
 
However, this dose is used frequently for postoperative or chemotherapy-induced nausea and 
vomiting, and is considered safe. In previous studies with 16mg intravenous ondansetron 
administration, no patient had arrhythmias or other serious side effects; headache and malaise were 
the main adverse effects [8, 9]. No psychological risks to subjects are envisioned. 
 
 
3.3.2 Other Potential Risks 
Intravenous catheter placement can cause a bruise. The amount of blood drawn is approximately 35cc 
and will not constitute a risk to subjects since this amount is well below the recommended limits for 
this population. Spinous catheter placement is a part of the routine perioperative care in this patient 
group; therefore there is no additional risk as a result of study participation. The collection of a 4mL 
CSF sample will be performed by an anesthesiologist immediately following spinal needle insertion 
for standard of care anesthesia. This additional collection of CSF is not expected to increase the risk 
of post-dural puncture headache, but it may occur, especially in younger patients. No psychological 
risks to subjects are envisioned. Subjects may experience a loss of confidentiality.  Investigators will 
keep subjects’ participation confidential to the extent permitted by law.  However, it is possible that 
others may become aware of subjects’ participation in this study and may inspect and copy records 
pertaining to this research.  Some of these records could contain information that personally identifies 
subjects. The results of genotyping will not result in identifiable, clinically diagnostic genetic 
information that has a known association with a medical condition. The data from the analysis will 
not be included in the patients’ medical records. 
 
3.4 Procedures to Minimize Potential Risks 
Studies are conducted in the Washington University Clinical Research Center under the supervision 
of the PI and Co-investigators. The PI is trained and experienced in performing research in human 
subjects, and the co-investigators are board-certified anesthesiologists with extensive clinical and 
research experience in the perioperative setting. 
Subjects are also continuously monitored by trained research (RN) nursing personnel throughout the 
study session and by their clinical team during surgery and recovery in the Past Anesthesia Care Unit 
(PACU),  as a part of routine care. Subjects will be monitored by electrocardiogram for any potential 
cardiac abnormalities associated with ondansetron administration.  Full patient monitoring and 
resuscitation capabilities are immediately available. 
The 16mg dose of ondansetron, when infused over 15 minutes  in adults 18-74 years old, was shown 
not to increase the QTc interval by more than 10ms, even if additional two doses of 8mg are 
administered later in the day [18]. Based on these data, and the current FDA recommendation, we 
will administer 16mg dose by 15-min infusion, and apply an upper age limit of 70 years on the study 
population. 


 
Simon Haroutounian, PhD © 
11 
 
Inclusion and exclusion criteria, monitoring, and the clinical protocol are designed to ensure that risks 
are absolutely minimal. Subjects are informed that participation is voluntary and they may refuse to 
participate and may withdraw from the study at any time without penalty. A pregnancy test will be 
performed on women of childbearing potential and subjects excluded if pregnant. Subjects will be 
told that in the event of a physical injury as the direct result of study procedures, they will be cared 
for by a member of the investigating team at no cost, within the limits of the Washington University 
compensation plan. 
 
With regard to confidentiality; 1) all subjects will be assigned a study ID number, 2) Samples will be 
kept confidentially.  They will be coded, with a key to the code linking code numbers to names kept 
at a separate location, under lock and key.  3) The link to identifiers will be destroyed at the end of 
the study. 4) Data will be stored under lock and key (office, file cabinet) and only the investigators 
and research team will have access.  If data are published, there will be no link to identifiers.  Study 
data will not be revealed to any organization, individuals other than the subjects, or the subjects 
themselves. 5) Study data will not be entered in subjects' medical records.  
 
3.5   Data and Safety Monitoring Plan 
The specific monitoring plan for this investigation is commensurate with the risks and the size and 
complexity of the investigations planned. The potential risks are attributable to the ondansetron 
infusion. Based on these considerations, the monitoring plan involves engaging a colleague from the 
Department of Anesthesiology not involved in the study to serve in a monitoring capacity. Based on 
the relatively low risks nature of the protocol, only a third person (the colleague), rather than a full 
Data Safety Monitoring Board will be used. The colleague will be an anesthesiologist knowledgeable 
in the risks associated with 5HT3 antagonist administration. This individual will review the annual 
summary of adverse events. In addition, this colleague will review all reports of a Serious Adverse 
Event, or an Unexpected Adverse Event. 
 
4.  HUMAN SUBJECTS RESEARCH 
 
4.1 Protection of Human Subjects 
The study will be conducted under appropriate Washington University Institutional Review Board 
protocols and consent forms approvals.  The study will be conducted under the supervision of the PI, 
a licensed pharmacist with several years of experience in the conduct of human studies, and the co-
PIs, board-certified anesthesiologists with many years of experience in spinal and regional anesthesia 
for surgeries. 
 
4.2 Sources of Materials 
Subjects will be recruited from Washington University Orthopedics and the Center for Perioperative 
Assessment and Planning (CPAP), as well as from BJH Surgery registration and the preoperative 
holding area. 
 
Data on comorbidities and concomitant medication use are provided by subjects. Specimens include 
blood obtained for transporter genotyping and for determining ondansetron plasma concentration.  
CSF samples are obtained for determining ondansetron CSF concentration. 
 


 
Simon Haroutounian, PhD © 
12 
 
4.3 Recruitment and Informed Consent 
Participants will be recruited primarily through Washington University Orthopedics and the Center 
for Perioperative Assessment and Planning (CPAP). 
Two primary recruitment mechanisms will be utilized: 
1. Participants will be referred from Washington University Orthopedics by the corresponding 
physicians. Interested subjects will contact the investigators.  
2. A weekly list of patients scheduled for CPAP visit before knee or hip arthroplasty will be 
generated from SIS system. The potential subjects will be approached by the study 
coordinator for inclusion consideration. 
Subjects may also be consented in the surgery registration area and the preoperative holding area. 
Subjects will be given verbal (initially) and then written descriptions of the study aims, procedures, 
risks, and benefits, and will be required to give written informed consent. A member of the 
investigative team provides all study descriptions, informed consent, and answers all questions. 
Subjects are informed verbally and in writing that participation is voluntary and they may refuse to 
participate and may withdraw from the study at any time without penalty. Subjects that participate, 
but do not complete all study procedures because their surgery is cancelled or rescheduled by their 
treating physician may re-consent to participate and be re-enrolled as long as there has been a 
minimum of 48 hours between the last study procedure and the re-consent event.  
 
4.4 Potential Benefits of the Proposed Research to the Subjects and Others 
We do not know if the patients will benefit from the intervention. Perioperative ondansetron 
administration may decrease postoperative nausea and vomiting, and is used as standard of care in 
this setting.  
Potential understanding of which patients are more likely to have higher CSF concentration of 
ondansetron may lead to introducing a potential analgesic treatment, from which patients with 
neuropathic pain may benefit in the future. 
The society may benefit from a new approach of treating neuropathic pain with CNS-penetrating 
5HT3R antagonists. 
 
4.5 Inclusion of Women 
Studies actively encourage the participation of women in the research. As a matter of operational 
policy, our studies routinely and deliberately attempt to include equivalent numbers of women and 
men. However, the nature of the current study precludes enrollment of a set number of female or 
male patients since the main criteria for inclusion is  hip or knee replacement surgery. Women of 
childbearing potential are not excluded from our research protocols.  
 
4.6 Inclusion of Minorities 
All of our studies actively encourage the participation of minorities in the research.  Our minority 
recruiting typically matches the demographic composition of the Washington University community 
from which subjects will be recruited (78% white, 21% Black, <1 % Hispanic). 
 
4.7 Inclusion of Children 
Children <18 yr will not be studied in this investigation. Children rarely undergo hip or knee 
replacement procedures. Including children may expose them to an unnecessary risk without the 
benefit of generalizability of the results. 
 


 
Simon Haroutounian, PhD © 
13 
 
 
Additional Collaborators: 
Chris Sawyer, PhD 
Washington University Genome Technology Access Center (GTAC) 
St Louis, MO 
Role: SNP genotyping 
 
Leonid Kagan, PhD 
Department of Pharmaceutics, Ernest Mario School of Pharmacy 
Rutgers, The State University of New Jersey 
Piscataway, NJ 
Role: Assistance with Pharmacokinetic modeling 
 
Only the PI, the co-PIs, and the research coordinators will have access to patient identifiers or PHI. 
The external collaborators will be blinded to any patient identifying information. 
 
5.  REFERENCES 
1. 
Dogrul, A., M.H. Ossipov, and F. Porreca, Differential mediation of descending pain 
facilitation and inhibition by spinal 5HT-3 and 5HT-7 receptors. Brain Res, 2009. 1280: p. 
52-9. 
2. 
Suzuki, R., et al., Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its 
treatment with gabapentin. Pain, 2005. 117(3): p. 292-303. 
3. 
Bannister, K., et al., Diffuse noxious inhibitory controls and nerve injury: restoring an 
imbalance between descending monoamine inhibitions and facilitations. Pain, 2015. 156(9): 
p. 1803-11. 
4. 
Kimura, M., H. Obata, and S. Saito, Peripheral nerve injury reduces analgesic effects of 
systemic morphine via spinal 5-hydroxytryptamine 3 receptors. Anesthesiology, 2014. 121(2): 
p. 362-71. 
5. 
Oatway, M.A., Y. Chen, and L.C. Weaver, The 5-HT3 receptor facilitates at-level mechanical 
allodynia following spinal cord injury. Pain, 2004. 110(1-2): p. 259-68. 
6. 
Marchi, N., et al., Determinants of drug brain uptake in a rat model of seizure-associated 
malformations of cortical development. Neurobiol Dis, 2006. 24(3): p. 429-42. 
7. 
Schinkel, A.H., et al., P-glycoprotein in the blood-brain barrier of mice influences the brain 
penetration and pharmacological activity of many drugs. J Clin Invest, 1996. 97(11): p. 2517-
24. 
8. 
McCleane, G.J., R. Suzuki, and A.H. Dickenson, Does a single intravenous injection of the 
5HT3 receptor antagonist ondansetron have an analgesic effect in neuropathic pain? A 
double-blinded, placebo-controlled cross-over study. Anesth Analg, 2003. 97(5): p. 1474-8. 
9. 
Tuveson, B., A.S. Leffler, and P. Hansson, Ondansetron, a 5HT3-antagonist, does not alter 
dynamic mechanical allodynia or spontaneous ongoing pain in peripheral neuropathy. Clin J 
Pain, 2011. 27(4): p. 323-9. 
10. 
Corrigan, B.W., et al., Heterogeneity in systemic availability of ondansetron and granisetron 
following oral administration. Drug Metab Dispos, 1999. 27(1): p. 110-2. 
11. 
Babaoglu, M.O., et al., Association of the ABCB1 3435C>T polymorphism with antiemetic 
efficacy of 5-hydroxytryptamine type 3 antagonists. Clin Pharmacol Ther, 2005. 78(6): p. 619-
26. 


 
Simon Haroutounian, PhD © 
14 
 
12. 
Tzvetkov, M.V., et al., Effects of OCT1 polymorphisms on the cellular uptake, plasma 
concentrations and efficacy of the 5-HT(3) antagonists tropisetron and ondansetron. 
Pharmacogenomics J, 2012. 12(1): p. 22-9. 
13. 
Tzvetkov, M.V., et al., The effects of genetic polymorphisms in the organic cation 
transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol 
Ther, 2009. 86(3): p. 299-306. 
14. 
Vasilopoulos, Y., et al., A pharmacogenetic study of ABCB1 polymorphisms and cyclosporine 
treatment response in patients with psoriasis in the Greek population. Pharmacogenomics J, 
2014. 
15. 
Fukudo, M., et al., Population pharmacokinetics/pharmacodynamics of erlotinib and 
pharmacogenomic analysis of plasma and cerebrospinal fluid drug concentrations in 
Japanese patients with non-small cell lung cancer. Clin Pharmacokinet, 2013. 52(7): p. 593-
609. 
16. 
Har-Even, R., et al., Plasma and cerebrospinal fluid concentrations of ibuprofen in pediatric 
patients and antipyretic effect: Pharmacokinetic-pharmacodynamic modeling analysis. J Clin 
Pharmacol, 2014. 54(9): p. 1023-30. 
17. 
VanDenBerg, C.M., et al., Pharmacokinetics of three formulations of ondansetron 
hydrochloride in healthy volunteers: 24-mg oral tablet, rectal suppository, and i.v. infusion. 
Am J Health Syst Pharm, 2000. 57(11): p. 1046-50. 
18. 
Zuo, P., et al., Integration of modeling and simulation to support changes to ondansetron 
dosing following a randomized, double-blind, placebo-, and active-controlled thorough QT 
study. J Clin Pharmacol, 2014. 
 

ICF_000.pdf: 
 
FOR IRB USE ONLY 
IRB ID #: 201605080 
APPROVAL DATE: 05/04/17 
RELEASED DATE: 05/04/17 
EXPIRATION DATE: 05/03/18 
 
INFORMED CONSENT DOCUMENT 
 
Project Title: 
Investigation of cerebrospinal fluid (CSF) pharmacokinetics of ondansetron 
 
Principal Investigator: 
Simon Haroutounian, PhD 
 
Research Team Contact: 
Karen Frey, 314 454-5980 
 
This consent form describes the research study and helps you decide if you want to participate.  It 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights and responsibilities as a research participant. By signing this 
form you are agreeing to participate in this study. 
 You should read and understand the information in this document including the procedures, 
risks and potential benefits.  
 If you have questions about anything in this form, you should ask the research team for more 
information before you agree to participate.   
 You may also wish to talk to your family or friends about your participation in this study. 
 Do not agree to participate in this study unless the research team has answered your 
questions and you decide that you want to be part of this study.  
 
WHAT IS THE PURPOSE OF THIS STUDY? 
This is a research study.  We invite you to participate in this research study because you are a healthy 
person and are scheduled to have hip or knee surgery with spinal anesthesia.   
 
The purpose of this research study is find out how much of a drug called ondansetron circulates in your 
blood and how much circulates in your spinal fluid after it is given IV (intravenously). Ondansetron is 
an FDA-approved drug that is routinely used to treat nausea and vomiting caused by surgery or cancer 
treatment.  If you choose to participate in this study, the time you will receive this drug before surgery 
will be determined by the study procedures described below. You may also receive this drug following 
surgery, if needed for nausea and vomiting, and if considered necessary by your clinical team.  
 
The purpose of this research study is also to see if ondansetron may be potentially helpful in treating 
people who have pain due to nerve damage. This study will help us understand whether ondansetron 
reaches the spinal fluid, and the way by which ondansetron may relieve pain from damaged nerves.  
 
Ondansetron is considered investigational, which means that it has not been approved by the U.S. Food 
and Drug Administration.  This is because the 16mg ondansetron dose in this study, which is approved 
for the prevention of nausea and vomiting after chemotherapy, has not been approved by the U.S. Food 
and Drug Administration for preventing nausea and vomiting after surgery.    
 
 
WHAT WILL HAPPEN DURING THIS STUDY? 
After you sign the consent, if you have a history of liver or kidney disease, we may do some additional 
blood tests to make sure you can continue in this study. One sample of 5ml (approximately 1 teaspoon) 
would be taken for this purpose. These tests will look for things such as liver of kidney failure. If you 
have a history of any irregular heart rate or rhythm, you may undergo an electrocardiogram (ECG) to 


 
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RELEASED DATE: 05/04/17 
EXPIRATION DATE: 05/03/18 
 
10.18.16 
 
Page 2 of 8 
check your heart. An ECG involves electrodes (sticky patches) being attached to your chest, arms and 
legs to monitor your heart activity while you lay still for a few minutes. If you have not had a pregnancy 
test, and you are a woman of childbearing potential, you will have a pregnancy urine test to ensure you 
are not pregnant. These additional tests may be performed at the time of your consent or on the day of 
surgery.   
 
On the day of your surgery, a research team member will meet you in pre-operative holding area.  You 
may be asked to arrive a little earlier to perform the research study procedures. You will have an IV 
[intravenous catheter] inserted in each arm.  One will be used by your surgical care team to give you 
fluids and anesthesia during your surgery and the other will be used for collecting blood samples for this 
research study.   
 
The study drug, ondansetron, will be given to you through the IV as an infusion lasting 15 minutes. This 
will start at 30, 60 or 120 minutes before your anesthesiologist begins the spinal anesthesia which is 
your routine care. The timing will be determined by randomization (similar to flipping a coin). A trained 
member of the research team will collect up to six blood samples from your IV immediately before the 
ondansetron infusion and at approximately 15, 30, 60, 120 and 180 minutes. Each sample is 
approximately 1 teaspoon. We will also collect 1 additional teaspoon of blood for genetic analysis to see 
if your genes play a role in how your body metabolizes ondansetron. Genetic analysis studies your DNA 
to look for mutations (changes) that may affect the way a person responds to treatment. 
 
A research nurse, who will be with you in the holding area during the study treatment, will be collecting 
the research blood samples and monitoring your heart rate and blood pressure during the infusion. 
 
Once the spinal needle is inserted for your anesthesia as a part of your routine care, a small sample of 
your spinal fluid, about 4mL, which is less than a teaspoon, will be collected. 
 
Will you save my research data to use in future research studies?  
As part of this study, we are obtaining data from you. We would like to use this data for studies going on 
right now as well as studies that are conducted in the future.  These studies may provide additional 
information that will be helpful in understanding pain from nerve damage, or other diseases or 
conditions, including research to develop investigational tests, treatments, drugs or devices that are not 
yet approved by the U.S. Food and Drug Administration.  It is unlikely that what we learn from these 
studies will have a direct benefit to you.  There are no plans to provide financial compensation to you 
should this occur.  By allowing us to use your data, you give up any property rights you may have in the 
data. 
 
If you change your mind and do not want us to store and use your data for future research you should 
contact the research team member identified at the top of this document. The data will no longer be used 
for research purposes. However, if some research with your data has already been completed, the 
information from that research may still be used. Also, if the data has been shared with other researchers 
it might not be possible to withdraw the data to the extent it has been shared. 
 
HOW MANY PEOPLE WILL PARTICIPATE? 
Approximately 30 people will take part in this study conducted by investigators at Washington 
University. 


 
FOR IRB USE ONLY 
IRB ID #: 201605080 
APPROVAL DATE: 05/04/17 
RELEASED DATE: 05/04/17 
EXPIRATION DATE: 05/03/18 
 
10.18.16 
 
Page 3 of 8 
 
HOW LONG WILL I BE IN THIS STUDY? 
If you agree to take part in this study, your involvement will last for approximately 3 hours on the day of 
your surgery. If blood tests or ECG are required, this may add additional 10-15 minutes of involvement.  
 
WHAT ARE THE RISKS OF THIS STUDY? 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study.  
 
Ondansetron 
Likely / Common  
Mild 
 diarrhea 
 constipation 
 headache 
 dry mouth 
 tiredness 
 
Less Likely / Less Common 
Mild 
 elevated liver function tests, which means the liver may not be functioning properly and can 
cause fatigue and jaundice (yellowing of the skin and eyes) 
 
Rare   
Serious 
 Serious irregular heartbeats 
 Low potassium in the blood, which can increase the risk of irregular heartbeats 
 Fever 
 Severe allergic reaction, such as rash, hives, fever, difficulty breathing, and low blood pressure 
 Seizures 
 Temporary blindness 
 
Intravenous catheter placement 
Likely / Common  
 Bruising at the site of placement 
 
Rare 
 Infection at the site of placement or in the blood stream. 
 
Blood Drawing 
The blood draw may cause bleeding, bruising, or pain.  Some people become dizzy or feel faint. There is 
also a rare risk of infection. 
 


 
FOR IRB USE ONLY 
IRB ID #: 201605080 
APPROVAL DATE: 05/04/17 
RELEASED DATE: 05/04/17 
EXPIRATION DATE: 05/03/18 
 
10.18.16 
 
Page 4 of 8 
Collection of cerebral spinal fluid 
Less likely/less common 
 Headache after the surgery 
 
ECG 
You may develop a mild rash where the electrodes (sticky patches) are attached.  
 
Women Capable of Becoming Pregnant 
If you are a woman capable of becoming pregnant, we will ask you to have a pregnancy test before 
beginning this study.  You cannot participate in the study if you are pregnant, as, there may be unknown 
risks to your unborn child, or risks to your unborn child that we did not anticipate.  If you believe or 
know you have become pregnant while participating in this research study, please contact the research 
team member identified at the top of this document as soon as possible.  Please discuss with the research 
team how long you need to wait before becoming pregnant after completing the treatment or procedures 
on this study. 
 
Genetics 
There is a federal law called the Genetic Information Nondiscrimination Act (GINA). In general, this 
law makes it illegal for health insurance companies, group health plans and employers with greater than 
15 employees to discriminate against you based on your genetic information. However, it does not 
protect you against discrimination by companies that sell life insurance, disability insurance or long 
term-care insurance.  
 
Breach of Confidentiality 
One risk of participating in this study is that confidential information about you may be accidentally 
disclosed.  We will use our best efforts to keep the information about you secure.  Please see the section 
in this consent form titled “How will you keep my information confidential?” for more information. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
You will not benefit from being in this study. 
 
However, we hope that, in the future, other people might benefit from this study if we discover a 
different therapy for people that suffer from pain due to nerve damage. 
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
You will not have any costs for being in this research study. 
 
You and/or your medical/hospital insurance provider will remain responsible for your regular medical 
care expenses. 
 
WILL I BE PAID FOR PARTICIPATING? 
You will be paid for being in this research study. You will need to provide your social security number 
(SSN) in order for us to pay you. You may choose to participate without being paid if you do not wish to 
provide your social security number (SSN) for this purpose.  If your social security number is obtained 
for payment purposes only, it will not be retained for research purposes.    
 


 
FOR IRB USE ONLY 
IRB ID #: 201605080 
APPROVAL DATE: 05/04/17 
RELEASED DATE: 05/04/17 
EXPIRATION DATE: 05/03/18 
 
10.18.16 
 
Page 5 of 8 
You will receive a $100 Target gift card for being in this research study. You will receive the gift card 
after the surgery while still in the hospital. If you complete the screening procedure, but cannot 
participate because of your blood, pregnancy or ECG test results, you will receive a $25 Target gift card.  
 
WHO IS FUNDING THIS STUDY? 
The University and the research team are not receiving payment from other agencies, organizations, or 
companies to conduct this research study.  
 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
Washington University investigators and staff will try to reduce, control, and treat any complications 
from this research. If you feel you are injured because of the study, please contact the investigator Dr. 
Simon Haroutounian at 314 286-1715 or by pager at 314-419-5583 and/or the Human Research 
Protection Office at 1-(800)-438-0445.  
 
Decisions about whether payment for medical treatment for injuries relating to your participation in 
research will be made by Washington University. If you need to seek medical care for a research-related 
injury, please notify the investigator as soon as possible.  
 
HOW WILL YOU KEEP MY INFORMATION CONFIDENTIAL? 
We will keep your participation in this research study confidential to the extent permitted by law.  
However, it is possible that other people such as those indicated below may become aware of your 
participation in this study and may inspect and copy records pertaining to this research.  Some of these 
records could contain information that personally identifies you.  
 Government representatives, (including the Office for Human Research Protections) to complete 
federal or state responsibilities 
 The U.S. Food and Drug Administration 
 Hospital or University representatives, to complete Hospital or University responsibilities 
 Information about your participation in this study may be documented in your health care records 
and be available to your health care providers who are not part of the research team.  
 The last four digits of your social security number may be used in hospital or University systems 
to track billing information for research procedures 
 Washington University’s Institutional Review Board (a committee that oversees the conduct of 
research involving human participants) and the Human Research Protection Office. The 
Institutional Review Board has reviewed and approved this study. 
 
To help protect your confidentiality, you will be assigned a study ID number and we will use that ID to 
manage all your study related information and blood samples.  Additionally, the key to the ID code 
linking code numbers to names will be kept at a separate location, under lock and key, and only the 
research team will have access to it.  We will destroy the link between your ID and your identifiers at 
the end of the study.  If we write a report or article about this study or share the study data set with 
others, we will do so in such a way that you cannot be directly identified. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 


 
FOR IRB USE ONLY 
IRB ID #: 201605080 
APPROVAL DATE: 05/04/17 
RELEASED DATE: 05/04/17 
EXPIRATION DATE: 05/03/18 
 
10.18.16 
 
Page 6 of 8 
 
Are there additional protections for my health information? 
Protected Health Information (PHI) is health information that identifies you. PHI is protected by federal 
law under HIPAA (the Health Insurance Portability and Accountability Act). To take part in this 
research, you must give the research team permission to use and disclose (share) your PHI for the study 
as explained in this consent form.  The research team will follow state and federal laws and may share 
your health information with the agencies and people listed under the previous section titled, “How will 
you keep my information confidential?” 
 
Once your health information is shared with someone outside of the research team, it may no longer be 
protected by HIPAA.   
 
The research team will only use and share your information as talked about in this form or as permitted or 
required by law.  When possible, the research team will make sure information cannot be linked to you 
(de-identified).  Once information is de-identified, it may be used and shared for other purposes not 
discussed in this consent form. If you have questions or concerns about your privacy and the use of your 
PHI, please contact the University’s Privacy Officer at 866-747-4975.  
 
Although you will not be allowed to see the study information, you may be given access to your health 
care records by contacting your health care provider.  
 
If you decide not to sign this form, it will not affect 
 your treatment or the care given by your health provider. 
 your insurance payment or enrollment in any health plans.   
 any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
 You authorize the use of your PHI for this research 
 This authorization does not expire. 
 You may later change your mind and not let the research team use or share your information 
(you may revoke your authorization).  
 To revoke your authorization, complete the withdrawal letter, found in the Participant section 
of the Human Research Protection Office website at 
http://hrpo.wustl.edu/participants//withdrawing-from-a-study/ or you may request that the 
investigator send you a copy of the letter.    
 
 
 
o If you revoke your authorization: 
 The research team may only use and share information already collected for 
the study. 
 Your information may still be used and shared as necessary to maintain the 
integrity of the research, for example, to account for a participant’s 
withdrawal from the research study or for safety reasons. 
 You will not be allowed to continue to participate in the study. 
 


 
FOR IRB USE ONLY 
IRB ID #: 201605080 
APPROVAL DATE: 05/04/17 
RELEASED DATE: 05/04/17 
EXPIRATION DATE: 05/03/18 
 
10.18.16 
 
Page 7 of 8 
IS BEING IN THIS STUDY VOLUNTARY? 
Taking part in this research study is completely voluntary.  You may choose not to take part at all.  If 
you decide to be in this study, you may stop participating at any time. Any data that was collected as 
part of your participation in the study will remain as part of the study records and cannot be removed.   
 
If you decide not to be in this study, or if you stop participating at any time, you won’t be penalized or 
lose any benefits for which you otherwise qualify.   
 
What if I decide to withdraw from the study? 
You may withdraw by telling the study team you are no longer interested in participating in the study or 
you may send in a withdrawal letter. A sample withdrawal letter can be found at 
http://hrpo.wustl.edu/participants/ under Withdrawing from a Research Study. 
 
Will I receive new information about the study while participating? 
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
 
Can someone else end my participation in this study? 
Under certain circumstances, the investigator or your doctors might decide to end your participation in 
this research study earlier than planned.  This might happen for no reason or because in our judgment it 
would not be safe for you to continue.  
 
WHAT IF I HAVE QUESTIONS? 
We encourage you to ask questions.  If you have any questions about the research study itself, please 
contact: Karen Frey at 314 454-5980 or Dr. Simon Haroutounian at 314 286-1715 or by pager at 314-
419-5583.  If you experience a research-related injury, please contact: Dr. Simon Haroutounian at 314 
286-1715 or by pager at 314-419-5583. 
 
If you have questions, concerns, or complaints about your rights as a research participant, please contact 
the Human Research Protection Office at 660 South Euclid Avenue, Campus Box 8089, St. Louis, MO  
63110, 1-(800)-438-0445, or email hrpo@wustl.edu.   General information about being a research 
participant can be found on the Human Research Protection Office web site, http://hrpo.wustl.edu.  To 
offer input about your experiences as a research participant or to speak to someone other than the 
research staff, call the Human Research Protection Office at the number above. 
 
 
This consent form is not a contract. It is a written explanation of what will happen during the study if 
you decide to participate. You are not waiving any legal rights by agreeing to participate in this study. 
As a participant you have rights and responsibilities as described in this document and including: 
 To be given enough time before signing below to weigh the risks and potential benefits and 
decide if you want to participate without any pressure from the research team or others. 
 To understand all of the information included in the document, have your questions answered, 
and receive an explanation of anything you do not understand. 
 To follow the procedures described in this document and the instructions of the research team to 
the best of your ability unless you choose to stop your participation in the research study. 


 
FOR IRB USE ONLY 
IRB ID #: 201605080 
APPROVAL DATE: 05/04/17 
RELEASED DATE: 05/04/17 
EXPIRATION DATE: 05/03/18 
 
10.18.16 
 
Page 8 of 8 
 To give the research team accurate and complete information. 
 To tell the research team promptly about any problems you have related to your participation, or 
if you are unable to continue and wish to stop participating in the research study. 
 
Your signature indicates that this research study has been explained to you, that your questions have 
been answered, and that you agree to take part in this study.  You will receive a signed and dated copy 
of this form. 
 
 
Do not sign this form if today’s date is after EXPIRATION DATE: 05/03/18. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Participant) 
 
 
 
 
(Date) 
 
 
____________________________________________ 
(Participant's name – printed) 
 
 
Statement of Person Who Obtained Consent 
 
The information in this document has been discussed with the participant or, where appropriate, with the 
participant’s legally authorized representative.  The participant has indicated that he or she understands 
the risks, benefits, and procedures involved with participation in this research study. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
 
(Date) 
 
 
___________________________________________ 
(Name of Person who Obtained Consent - printed)