Clinical trial NCT01990573
Conditions: Pain
Keywords: spinal surgery Methadone
Sponsor: Washington University School of Medicine
Start date: 2013-04-10; Completion date: 2018-06-30
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Three arm randomized controlled trial to evaluate the efficacy of a single dose of intraoperative methadone in reducing post-operative pain and opioid consumption in adolescents undergoing posterior spinal fusion. Our secondary goal is to determine the pharmacokinetics of IV methadone in children (0.3 and 0.4 mg/kg).

Detailed description:
Randomized, controlled, modified dose-escalation design. Patients receive standard monitoring for anesthesia and postoperative care. Surgical and anesthesia (except for opioid use) care are not altered for study purposes. All patients are induced by propofol and muscle relaxants. In the first cohort (n=30 evaluable), subjects are randomized 1:2 to either control (standard intraop opioid at anesthesiologists' discretion) or methadone HCl (0.4 mg/kg ideal body weight, IBW). In the second cohort (n=30 evaluable), subjects are randomized 1:2 to either control (standard intraop opioid) or methadone HCl (0.3 mg/kg ideal body weight, IBW). Subjects in the study groups will receive methadone (IV bolus, after induction of anesthesia) as their primary intraoperative opioid, rather than leaving the choice of intraoperative opioid to the anesthesiologist. Intraoperative breakthrough pain will be treated at the discretion of the anesthesiologist with fentanyl. In the control groups, intraoperative opioid administration will be left at the discretion of the anesthesia providers. Patient controlled analgesia as prescribed by the clinical team, using hydromorphone or morphine, will be used to treat postoperative pain relief.

Arms: arm 1: 0.3mg/kg IV methadone HCl arm 2: 0.4mg/kg IV methadon HCl arm 3: control no methadone, standard of care opioids.
Interventions: intervention 1: 0.3mg/kg IV methadone HCl intervention 2: 0.4mg/kg IV methadon HCl intervention 3: control no methadone
Intervention descriptions: intervention 1: Group I will receive 0.3mg/kg IV methadone HCl intervention 2: Group II will receive 0.4mg/kg IV methadone HCl. intervention 3: The control group will not receive methadone.

Protocol documents:
Prot_SAP_001.pdf: 
CONFIDENTIAL: This document is the intellectual property of A. Sharma, MD, MBA, and E. Kharasch, MD, PhD. 
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Methadone in Pediatric Anesthesia II 
 
 
PI: Anshuman Sharma MD, MBA 
Associate Professor, 
Director of Quality Improvement, 
Department of Anesthesiology, BO 8054 
Tel: 314 454 2190 
anshumansharma@wustl.edu 
 
 
Co-PI:  Evan Kharasch, MD PhD 
Russell D. and Mary B. Shelden Professor of Anesthesiology 
Director, Division of Clinical and Translational Research 
Department of Anesthesiology, Box 8054 
T 314-362-8796 
F 314-362-8571 
kharasch@wustl.edu 
 
 
 
 
Co-Investigators:  Dr. Chuck Schrock MD 
Associate Professor of Anesthesiology 
Box 8054, 
Tel: 314 454 2190 
 
 
 
 
Original: 02/02/2013 
Amendment 1: 12/5/13 
Amendment 2: 4/16/14 
Amendment 3: 09/10/2014 


 
 
 
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Page 2 
 
Amendment 1, 12/5/2013: Administration of PROMIS questionnaire to be administered by the research 
team to the patient on a tablet device. 
Rationale: To help determine patient’s preoperative expectations and functional status as impacted by 
their medical condition requiring this surgical procedure. 
 
 


 
 
 
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Amendment 2, 4/16/2014: Administration of a questionnaire to the participant’s parent or legal guardian 
 
Rationale: To help determine from the primary caregiver the influence of the environment, social and 
psychological, on post-operative pain. 
 
 


 
 
 
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Amendment 3, 09/10/2014: Change in dosage range for intraoperative administration of methadone from 
0.4-0.5mg/kg Ideal Body Weight to 0.3 – 0.5mg/kg Ideal Body Weight (IBW) 
 
Rationale: Postoperative management of pain for the pediatric spinal surgery population has changed 
over the course of time since the completion of our last research project (HRPO# 201107357). The 
previous study had demonstrated that 0.3mg/kg methadone was not effective in reducing postoperative 
opioid consumption. Currently, patients are prescribed additional drugs such as gabapentin and 
methocarbamol, with potential for interaction with all opioids. Based on our observations with this 
current protocol to date, we anticipate that escalation of methadone dosages beyond 0.4mg/kg (ideal 
body weight) may not be required. We feel  that routine postoperative use of gabapentin and 
methocarbamol require re-evaluation of intraoperative methadone dosing at 0.3mg/kg (IBW) for this 
population under current standard of care pain management.  
 


 
 
 
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 Abstract 
 
The μ-opioid receptor agonist methadone is frequently used in adult anesthesia and adult pain 
therapy.  Methadone has an extremely long half-life, which confers therapeutic advantage by providing 
more stable plasma concentrations and long-lasting pain relief.  Methadone perioperative 
pharmacokinetics in adults is well characterized.  Methadone is also frequently used in children.  Previous 
work by our group demonstrated that pharmacokinetics of methadone in adolescents are very similar to 
that in adults, but that doses used for major spinal surgery (0.1-0.3 mg/kg) were insufficient to have a 
significant opioid-sparing effect. This current investigation aims to study opioid sparing effects of higher 
doses of methadone (0.3 - 0.5 mg/kg) in adolescents undergoing posterior spinal fusion. Additionally, we 
will determine the pharmacokinetics of the higher doses of IV methadone administered intra-operatively. 


 
 
 
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SYNOPSIS 
Study Title 
Methadone in Pediatric Anesthesia II 
Objective 
Multiple arm, randomized controlled trial to evaluate the efficacy of a single dose of intraoperative 
methadone in reducing post-operative pain and opioid consumption in adolescents undergoing 
posterior spinal fusion.  Our secondary goal is to determine the pharmacokinetics of IV methadone in 
children (0.3 - 0.5 mg/kg). 
Study Period 
Planned enrollment duration: Approximately 2 years. 
Planned study duration: Approximately 6 days per subject 
Number of Patients 
60 evaluable subjects 
Study Medication 
Administration 
60 evaluable patients will be randomized 2:1 to receive intraoperative IV methadone HCL, 0.3 – 
0.5mg/kg, or serve as controls and will not receive any methadone. Control subjects will receive 
standard of care treatment per the attending anesthesiologist. 
Study Design 
Randomized, controlled, modified, Dixon up and down dose-finding design (1). Patients receive 
standard monitoring for anesthesia and postoperative care. Surgical and anesthesia (except for opioid 
use) care are not altered for study purposes. All patients are induced by propofol and muscle relaxants. 
In the first cohort, subjects are randomized 1:2 to either control (standard intraop opioid at 
anesthesiologists’ discretion) or methadone HCl (0.4 mg/kg ideal body weight, IBW). Based on an 
interim analysis for the initial treatment dose (0.4mg/kg), the second cohort will be randomized 1:2 to 
either control (standard intraop opioid) or methadone HCl (0.3 mg/kg ideal body weight, IBW). 
Subjects in the study groups will receive methadone (IV bolus, after induction of anesthesia) as their 
primary intraoperative opioid, rather than leaving the choice of intraoperative opioid to the 
anesthesiologist. Intraoperative breakthrough pain will be treated at the discretion of the 
anesthesiologist with fentanyl. In the control groups, intraoperative opioid administration will be left at 
the discretion of the anesthesia providers. Patient controlled analgesia as prescribed by the clinical 
team, using hydromorphone or morphine, will be used to treat postoperative pain relief.  
Inclusion and 
Exclusion Criteria 
Inclusion Criteria 
1. Age 11-18 years 
2. Undergoing general anesthesia and idiopathic posterior spinal fusion surgery with anticipated 
postop inpatient stay of> 3 days 
3. Signed, written, informed consent from legal guardians and assent from patient 
Exclusion Criteria 
1. History of liver or kidney disease. 
2. Females who are pregnant or nursing. 
3. Developmental delay and/or neuromuscular scoliosis 
Measurements 
Total intraoperative and postoperative care unit (PACU) opioid administration will be recorded from 
the patient’s medical record.  Daily opioid consumption will be calculated from the PCA utilization 
and electronic medical records (EMRs) for up to 6 postoperative days. Pain intensity will be assessed 
using the Wong-Baker FACES scale.  Pain relief is also assessed using a Colored-Visual Analog Scale.  
Blood and urine samples will be collected for 96 hrs after methadone dosing for determination of 
methadone and metabolite concentrations by HPLC-mass spectrometry.  Subjects will be genotyped for 
major polymorphisms of the methadone metabolizing enzyme CYP2B6. 
Statistical 
Methodology 
Demographics data including race, sex, and age will be analyzed. Baseline characteristics of the cohort 
will be described. Results will be expressed as the mean and standard deviation. 
Outcomes 
Primary: Intraoperative, postoperative and daily cumulative opioid utilization    
Secondary: Methadone and metabolite enantiomers plasma AUC, maximum concentration, metabolite 
/methadone AUC ratios, metabolite formation clearance correlation of methadone enantiomer 
clearances and metabolite formation clearances, influence of CYP2B6*6 hetero or homozyge genotype 


 
 
 
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on above primary and secondary outcomes 
 
1. Specific Aims. 
1.1.  To study the effects of a single dose of methadone on postoperative pain and opioid 
consumption in pediatric surgical patients. 
1.2. Determine the pharmacokinetics of IV methadone (0.3-0.5 mg/kg) in children 
1.3. Determine cytochrome P4502B6 (CYP2B6) genotype in patients receiving methadone, and any 
relationship to methadone clearance. 
1.4. Determine from the primary caregiver the influence of the environment, social and 
psychological, on post-operative pain. 
2. Background 
Inadequate pain relief has a significant psychological impact upon children, including alterations 
in their perceptions of future painful experiences and medical procedures (1). The psychological 
ramifications of pediatric pain include posttraumatic stress disorder, lack of adherence to treatment, poor 
coping skills, changes in accuracy in the self-report of pain, and lack of trust in health-care providers (2). 
The degree to which this pain is controlled impacts the ability of patients to cope with the next pain 
episode. Patients undergoing major spine surgery experience severe pain in the postoperative period, 
which may increase morbidity and the incidence of complications, as well as prolong postoperative 
rehabilitation. Postoperative pain itself is a risk factor for development of chronic pain syndromes(3,4). 
Methadone is a µ opioid agonist which is highly efficacious in the treatment of acute, chronic, 
neuropathic, and cancer pain(5).  In adults it is increasingly being used as a first-line analgesic.  
Methadone is highly efficacious in adult anesthesia and postoperative pain(6,7). The typical dose for adult 
anesthesia is 20 mg (nominally 0.3 mg/kg) at the beginning of anesthesia.  Methadone is advantageous 
because it has slow elimination, resulting in prolonged effect and significantly diminished need for 
postoperative analgesics.  Reducing postop opioid analgesic use also decreases the potential for opioid-
related side effects.  Methadone has a long half-life, averaging 24-36 hours in healthy adults and 
adolescent patients (12).  It has no active metabolites or pro-drug forms.  Methadone is metabolized in the 
liver by cytochrome P450 CYP2B6 (8–10). Methadone is also widely used in children, particularly in 
pain treatment(11). In infants and children younger than 10 yrs (mean age 4 yrs), the initial daily dose of 
methadone did not exceed 0.2–0.4 mg/kg/day, and daily methadone doses rarely exceeded 0.6 mg/kg.  
Perioperative analgesia remains a major challenge for physicians who care for patients 
undergoing complex spine surgery. Many patients are controlled by opioid analgesic that can result in 
postoperative adverse events. We propose to compare the two different doses of methadone in reducing 


 
 
 
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Page 8 
 
the postoperative opioid consumption and reduction in pain scores. 
A recent study by our group demonstrated that the pharmacokinetics of methadone enantiomer 
disposition in adolescents were similar to that of healthy adults (12). Another study by Stemland et al 
used a three compartmental model to analyze time-concentrations profile of single dose of 0.25mg/kg of 
methadone. They concluded that the pharmacokinetic profile in adolescents was similar to that of adults. 
They also observed a rapid redistribution after single bolus of methadone, hence producing inadequate 
plasma concentrations of the drug for postoperative analgesia. This suggests that in order to improve 
efficacy of methadone, higher dose than 0.3 mg/kg of methadone or continuous infusion of methadone 
may be needed (13). 
Evaluating the role of methadone in pediatric spinal surgery patients is advantageous because 1) 
high dose of opioids are routinely used during and after the surgery, 2) methadone is one of the 
commonly used opioids for this surgery, 3) an arterial catheter or a second IV catheter is needed for the 
surgery and can be used to draw blood samples, 4) prolonged analgesia from methadone is expected to 
decrease the need for additional opioids.  
Assessment of pain has become standard practice in the treatment of pediatric patients.  Several 
pain scales including the Wong-Baker FACES scale, the Oucher Scale and the Visual Analog Scale 
(VAS) have been USED in children who were experiencing pain (14,15).   
In this study, we propose to evaluate postoperative opioid consumption, pain intensity and pain 
relief in pediatric patients undergoing posterior spinal fusion who will receive a single dose of methadone 
during surgery.  In addition, we will study dose effect of ing various doses of methadone, between 0.3 – 
0.5mg/kg IBW. Secondarily, we will determine the pharmacokinetics of higher doses of IV methadone in 
children who are undergoing anesthesia and surgery.  Lastly, we will determine the role of CYP2B6 
genotype on methadone pharmacokinetics. 
3. Drug Information 
Methadone hydrochloride is a synthetic μ-agonist with multiple actions qualitatively similar to 
those of morphine.  Onset of effect is about 2-10 min for parenteral dosing.  Methadone is primarily 
metabolized by N-demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-
diphenylpyrrolidene (EDDP).  In vitro, cytochrome P450 enzymes, primarily CYP3A4 and CYP2B6 are 
responsible for conversion of methadone to EDDP and other inactive metabolites.  In vivo, CYP2B6 is a 
major determinant of metabolism to inactive metabolites which are excreted mainly in the urine.  The 
terminal half-life (T½) in healthy children averages 24-36 hrs. Like adults, in teenage children, most 
common side effect of methadone, like other opioids, is sedation, nausea and vomiting.  Respiratory 
depression is the chief hazard associated with methadone, like all opioids.  QT prolongation and serious 
arrhythmia have been observed during treatment with methadone and have been associated with doses 


 
 
 
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Page 9 
 
>200 mg/day(16).  
 
4. Eligibility 
4.1. Inclusion Criteria. 
4.1.1. Age 11-18 years 
4.1.2. Undergoing general anesthesia and idiopathic posterior spinal surgery with anticipated 
postop inpatient stay of > 3 days 
4.1.3. Signed, written, informed consent from legal guardians and assent from patient 
4.2. Exclusion Criteria. 
4.2.1. History of or known liver or kidney disease. 
4.2.2. Females who are pregnant or nursing. 
4.2.3. Children with developmental delay  
4.2.4. Children undergoing surgery for neuromuscular scoliosis 
5. Enrollment 
5.1. Subjects and parents/guardians will be approached prior to surgery.  Patients will be consented 
for participation and enrolled in the study by study personnel. 
6. Methods 
6.1. Preoperative and Intraoperative Period 
 
Parents and patients will be asked to complete a questionnaire prior to the child’s surgery. 
This will take approximately 5 minutes. Participants can choose to complete the survey and not 
participate in the randomized part of the study.  The questionnaire is to determine if factors such 
as anxiety and social economic attributes interact with each other prior to surgery.  If only 
participating in the questionnaire information regarding demographic data, pain scores and pain 
treatment will be collected from the patients’ medical record. 
 
Patients will receive standard physiologic monitoring for anesthesia and postoperative 
care.  Using a modified Dixon up and down dose finding method, subjects in the first cohort are 
randomized 1:2 to receive either control (standard intraop opioid) or methadone HCl (0.4 mg/kg 
ideal body weight, IBW).  In the second cohort, subjects are randomized 1:2 to receive either 
control (standard intraop opioid) or methadone HCl (0.3 mg/kg ideal body weight, IBW). 
Anesthesia and surgical care will not be altered for the purposes of this investigation, except that 
subjects in groups I and II, will receive methadone as their intraoperative opioid, rather than 
leaving the choice of intraoperative opioid to the anesthesiologist (patients typically may get 
methadone or any other opioid).  The control group patients will receive intraoperative analgesia 
with opioids other than methadone left at the discretion of their anesthesiologist. Additional 


 
 
 
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Page 10 
 
randomized cohorts may be included to study IV methadone HCl doses within the range of 0.3 – 
0.5mg/kg IBW, based on interim study findings and analysis. 
6.2.  Administration of Study Medication. 
 
Methadone is administered as an IV bolus after induction of anesthesia and after an 
arterial line is placed.  Methadone hydrochloride is available commercially as a solution for 
injection of 10 mg/ml. Based on our experience, we believe that additional postoperative 
opioids will still be needed, but that increasing methadone doses will result in lessened 
postoperative opioid use. 
6.3. Assessments. 
6.3.1. Pain Assessment – Acute postoperative pain will be managed by St. Louis Children’s 
Hospital pain services. Assessments are made in the postoperative period by a trained 
member of the research team blinded to intraoperative use of methadone. These will be 
conducted on each post-operative day until discharge or post op day 6, whichever comes 
first.  Pain intensity is assessed using the Wong-Baker FACES scale employed by the 
inpatient nursing staff and previously validated (9).  Pain relief is also assessed using a 
Colored-Visual Analog Scale.  Other questions regarding pain relief and comfort may be 
given using a tablet. Sedation is assessed using a five-point scale (patient fully alert – not 
arousable).  Itching and nausea are assessed using a five-point verbal scale (none, mild, 
moderate, severe or excruciating). 
6.3.2. Pharmacokinetics – Pharmacokinetics studies will be performed for all patients in 
methadone treatment groups.  Blood samples (approx 3 ml each) will be obtained before 
methadone and at approx 0.08, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hr after IV 
methadone administration. Blood samples will be drawn from the arterial line for the first 
24 hours and then from the venous lines or collected with routine labs. Total amount of 
blood drawn will be approx. 48 mls for pharmacokinetic testing for up to four days. Blood 
will only be collected while the patient is hospitalized; if the patient is discharged from the 
hospital no further collections will be made.  
6.3.3. CYP Genotyping – For all patients, 5 ml of blood will be drawn for CYP2B6 genotyping.  
Genotyping will be performed at the WUSTL Genome Technology Access Center (GTAC).  
6.3.4. Urine samples- For all patients, 24 hour- urine collections will be conducted for up to 96 
hours after surgery.  
6.4. Postoperative Period 
Patients receive standard of care analgesia using patient control analgesia method, primarily 
with hydromorphone or morphine as determined by the treating physician.  Postoperative 


 
 
 
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Page 11 
 
care is not altered for purposes of this study.  
7. Data Collection and Monitoring. 
7.1. Assessment of Pain Intensity and Pain Relief- Each pediatric patient enrolled in the study, 
regardless of type of opioid received, will have  pain intensity assessed each post operative 
hospital day (HD) for up to six days or until discharge, whichever comes first.  The Wong-Baker 
FACES scale and Verbal analogue scale, available as laminated cards, are currently used by the 
nursing staff to assess pain on the inpatient units.  Pain will also be assessed by patients using a 
colored-visual analogue scale. The study personnel performing the assessment will have a set 
script to read when administering the scale.  
7.2. Opioid Consumption. The inpatient medical record will be used to calculate the amount of 
morphine or morphine equivalents administered for each 24-hour period that subjects are 
receiving opioid analgesics. Oral opioid administration will be totaled through discharge for each 
24-hour period as well. 
7.3. Other Required Studies. Required baseline measurements that will be obtained from the EMR 
are vital signs, weight, height, and peripheral oxygen saturation by pulse oximetry and are all 
collected as standard of care. 
7.4. Drug and metabolite concentrations and drug effects.  Plasma concentrations of methadone and 
the mono N-demethylated metabolite EDDP will be determined by HPLC-mass spectrometry. 
7.5. Sources of Research Material.  Background information including demographic data, outpatient 
medications used, and chronic medical conditions will be obtained from the medical record at 
the time of enrollment 
8. Data and Safety Monitoring Plan. 
In general, the PI has developed a specific set of Standard Operating Procedures (SOPs) for 
clinical research.  All individuals working under the PI are required to read and be totally 
familiar with and compliant with the SOPs.  The PI's SOPs are in part developed from and are 
compliant with the Institutional guidelines, including those for a) Interactions with the 
Washington University Human Subjects Review Committee, b) Informed Consent Development 
and Implementation, c) Subject Recruitment and Screening, d)  Subject Management While on 
Study, e) Adverse Event Reporting. 
8.1. 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 use of 
methadone.  Based on these considerations the monitoring plan involves engaging one colleague 
(a pediatric anesthesiologist, pediatrician or clinical pharmacologist knowledgeable in the 
pharmacology of opioids) not involved in the study to serve in a monitoring capacity.  Based on 


 
 
 
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the small size and relatively low risks nature of the protocol, only a third person (the colleague), 
rather than a full DSMB, is utilized.  This individual will review the annual summary of adverse 
events. In addition, they will review all reports of a Serious Adverse Event, or an Unexpected 
Adverse Event.   
8.2. The specific plan for submitting Adverse Event Reports to the IRB is detailed in the PI's SOP for 
Adverse Event Reporting. 
8.3. Off-Study Criteria: Participation will be terminated if requested by the patient or patient’s 
guardian(). 
8.4. Stopping Rules: The study will be temporarily suspended, pending a detailed review, if there is a 
Serious Adverse Event resulting from methadone. 
9. Statistical Methods 
9.1. Primary Assessment 
9.1.1. Overall morphine (equivalents) consumption for each patient during hospitalization 
9.1.2. Absolute pain scores and pain relief scores 
9.2. Secondary Assessments 
9.2.1. Methadone clearance 
9.2.2. Maximum plasma methadone concentration 
9.2.3. Area under the curve (AUC) of plasma EDDP vs time 
9.2.4. Maximum plasma EDDP concentration 
9.2.5. AUC (plasma EDDP)/AUC (plasma methadone) 
9.2.6. Cmax (plasma EDDP)/Cmax (plasma methadone) 
9.2.7. Urine concentration of methadone and EDDP  
9.2.8. Side effects of opioids 
9.3. Analysis.  
9.3.1. Sample Size- we decided to use our pilot study data which looked into the pharmacokinetics 
of methadone in pediatric surgical patients attending St. Louis Children Hospital. This is 
actually the pooling place for the present study and therefore the information provided is a 
“true” sample of the data to be collected. The pilot study revealed that patients undergoing 
spinal fusion surgery used an average of 274 mg of morphine equivalents within 72 hours 
post-surgery with a standard deviation of 82 mg. Based on this information and assuming a 
2-sided test of two independent sample means with α 0.05, we were able to estimate that the 
proposed study will have at least 80% power to detect 30% decrease in the total 
postoperative consumption of morphine or morphine equivalents among the patients 
assigned to the two treatment groups combined when compared to the control group 


 
 
 
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patients. Specifically, with a total sample of approx. 60 patients assigned equally across 
study groups (1:2 randomization), we will have adequate statistical power to detect a 
clinically meaningful reduction of opioid use in patients receiving a single dose of 
methadone before incision. 
To study the effect size between two groups, power calculations were made with 
alternative mean differences in morphine consumption over 72 hours post-surgery with 
assumed variation range and a 2-sided test with α = 0.05. Based on our conservative 
assumptions, we found that, with a sample as small as 20 in each group, we will have 80% 
power to detect a minimum difference between 10 and 20 mg of morphine use, depending 
on the observed variability between the two groups. 
9.3.2. Statistical Analysis- Baseline characteristics of the cohort will be described. Demographics 
data including race, sex, and age at study entry will be analyzed using chi-square and t- test 
appropriate. Total daily opioid consumption and pain scores using both Wong-Baker 
FACES and colored visual analogue scale, will be compared between the groups.  Outcome 
measures will be expressed by the mean and standard deviation. Group outcomes will be 
compared across the two or three groups, using t-test and/or analysis of variance, ANOVA 
and MANCOVA to account for potential cofounders. 
9.3.3. Methadone Calculations -Methadone and EDDP plasma concentration-time data will be 
analyzed by linear and nonlinear regression analysis using noncompartmental or 
compartment models to determine total area-under-the-curve (AUC), and systemic 
clearance.  Results will also be analyzed using population methods, with age and dose as 
covariates, to determine linearity of pharmacokinetic parameters and effects of age. 
10. Risk Assessment 
10.1. 
Methadone   The most common clinical effect of opioids such as methadone is mild 
sedation.  Based on prior experience with this opioid and doses, and prior published experience, 
some subjects might experience mild sedation for about 0.5-1 hr after methadone administration, 
were they awake.  Since patients will be anesthetized during this period, clinical methadone 
effects are expected to be no different from those of anesthesia and any other opioid 
administered during anesthesia.  We have further attempted to minimize the risk to the patients 
by following a conservative approach of two step randomization.  The most common adverse 
effect of methadone is nausea and/or vomiting.  Patients will have only clear liquids 6 hours 
before anesthesia, per standard of care.  If nausea and/or vomiting occur, they will be treated 
using the standard of care for all post-anesthesia nausea and vomiting.  Respiratory depression is 
a potential concern with all opioids, but has not been problematic at the doses of methadone that 


 
 
 
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Page 14 
 
have been used in similar previous studies.  Mild respiratory depression is defined as respiratory 
rate <8/min in adults and children older than 10, <12–16 in children age 3-10, and <20 in 
children younger than two.  Severe depression will be defined as the administration of naloxone 
to a patient with respiratory rate < 6/min.  If treatment is required, naloxone will be used.  
Patients in the hospital are routinely periodically monitored by blood pressure and/or pulse 
oximetry, and receive supplemental oxygen if dictated, according to good clinical practice.   
10.2. 
Genotyping – With regard to the determination of CYP2B genotype: 1) CYP2B genes are 
not associates with any disorder(s), syndrome(s), or adverse condition. 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) We have no evidence to suggest that testing will provide evidence of previously 
undiagnosed or unrecognized illness, or susceptibility to illness. 5) We will not use samples for 
any purpose other than to study genes related to the disposition and response to study drugs. 6) 
Blood samples will not be used to establish permanent cell lines. 7) Data will be stored under 
lock and key (office, file cabinet) and only the investigators 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. 8) We will not enter any genetic 
study data in subjects’ medical records. 9) Studies are not likely to result in findings that meet 
the National Bioethics Advisory Commission criteria for disclosure. 10) We will not have 
genetics counseling available to subjects, as they will not be informed of results and there are no 
know implications with respect to disease. 11) DNA samples will stripped of identifiers and 
given a separate code numbers unrelated to the subjects’ study identification numbers. The code 
key will be kept by the PI under lock and key. 
10.3. 
Special Precautions. Standard of care for all surgical patients includes placement of an 
IV, pulse oximetry, ECG and blood pressure monitoring. 
10.4. 
Procedures to Maintain Confidentiality. Any information that is obtained in connection 
with research that can be identified with a subject will remain confidential.  The consent form, 
medical information, flow-sheets, and pharmacokinetic and genetic data will be stored under 
lock and key (office, file cabinet) and only the PI,  physician investigators, and research team 
will have access..  Statisticians involved in the project will have access to de-identified data for 
the purposes of analysis.   
10.5. 
Risk/Benefit Assessment.  The dose of methadone given will be a standard analgesic dose, 
and it might provide longer pain relief. In addition, this study will result in increased awareness 
of standard of care and appropriate pain assessment in the nursing staff and treating physicians 


 
 
 
CONFIDENTIAL: This document is the intellectual property of Anshuman Sharma, MD and Evan Kharasch, MD, PhD. 
Acceptance of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
published or disclosed without prior written approval.  
Page 15 
 
that will benefit patients not enrolled on study. The risk of respiratory depression is no more than 
that expected from standard morphine therapy as the patients will only receive one dose of 
methadone and it will be at doses less than treatment doses. Understanding the pharmacokinetics 
of methadone in children will allow more appropriate dosing of methadone thereby increasing 
clinical pain relief and decreasing the risk of these toxicities. 
 
References: 
1.  Zempsky WT, Cravero JP. Relief of pain and anxiety in pediatric patients in emergency medical 
systems. Pediatrics. 2004 Nov;114(5):1348–56.  
2.  Stearns SD, Smith CA, Carter BD. Psychological ramifications of pediatric pain. Clinical Pediatric 
Emergency Medicine. 2000 Dec;1(5):299–305.  
3.  Sandkühler J. Fear the pain. Lancet. 2002 Aug 10;360(9331):426.  
4.  Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. 
Anesthesiology. 2000 Oct;93(4):1123–33.  
5.  Anghelescu DL, Faughnan LG, Hankins GM, Ward DA, Oakes LL. Methadone use in children and 
young adults at a cancer center: a retrospective study. J Opioid Manag. 2011 Oct;7(5):353–61.  
6.  Gourlay GK, Wilson PR, Glynn CJ. Pharmacodynamics and pharmacokinetics of methadone during 
the perioperative period. Anesthesiology. 1982 Dec;57(6):458–67.  
7.  Gourlay GK, Willis RJ, Wilson PR. Postoperative pain control with methadone: influence of 
supplementary methadone doses and blood concentration--response relationships. Anesthesiology. 
1984 Jul;61(1):19–26.  
8.  Kharasch ED, Hoffer C, Whittington D, Sheffels P. Role of hepatic and intestinal cytochrome P450 
3A and 2B6 in the metabolism, disposition, and miotic effects of methadone. Clin. Pharmacol. Ther. 
2004 Sep;76(3):250–69.  
9.  Totah RA, Sheffels P, Roberts T, Whittington D, Thummel K, Kharasch ED. Role of CYP2B6 in 
stereoselective human methadone metabolism. Anesthesiology. 2008 Mar;108(3):363–74.  
10.  Totah RA, Allen KE, Sheffels P, Whittington D, Kharasch ED. Enantiomeric metabolic interactions 
and stereoselective human methadone metabolism. J. Pharmacol. Exp. Ther. 2007 Apr;321(1):389–
99.  
11.  Shir Y, Rosen G, Zeldin A, Davidson EM. Methadone is safe for treating hospitalized patients with 
severe pain. Can J Anaesth. 2001 Dec;48(11):1109–13.  
12.  Sharma A, Tallchief D, Blood J, Kim T, London A, Kharasch ED. Perioperative pharmacokinetics of 
methadone in adolescents. Anesthesiology. 2011 Dec;115(6):1153–61.  
13.  Stemland CJ, Witte J, Colquhoun DA, Durieux ME, Langman LJ, Balireddy R, et al. The 


 
 
 
CONFIDENTIAL: This document is the intellectual property of Anshuman Sharma, MD and Evan Kharasch, MD, PhD. 
Acceptance of this document constitutes the agreement by the recipient that no unpublished information contained herein will be 
published or disclosed without prior written approval.  
Page 16 
 
pharmacokinetics of methadone in adolescents undergoing posterior spinal fusion. Paediatr Anaesth. 
2012 Sep 14 DOI: 10.1111/pan.12021 
14.  Luffy R, Grove SK. Examining the validity, reliability, and preference of three pediatric pain 
measurement tools in African-American children. Pediatr Nurs. 2003 Feb;29(1):54–9.  
15.  Moore A, Moore O, McQuay H, Gavaghan D. Deriving dichotomous outcome measures from 
continuous data in randomised controlled trials of analgesics: use of pain intensity and visual 
analogue scales. Pain. 1997 Feb;69(3):311–5.  
16.  Stringer J, Welsh C, Tommasello A. Methadone-associated Q-T interval prolongation and torsades de 
pointes. Am J Health Syst Pharm. 2009 May 1;66(9):825–33.  
 
 

ICF_000.pdf: 
 
FOR IRB USE ONLY 
 
IRB ID #: 201302099 
APPROVAL DATE: 01/31/17 
RELEASED DATE: 02/03/17 
EXPIRATION DATE: 01/30/18 
 
INFORMED CONSENT DOCUMENT 
 
Project Title: 
Methadone in Pediatric Anesthesia II 
 
Principal Investigator: 
Anshuman Sharma 
 
Research Team Contact: 
 Lindsay Juriga, 314-454-7945 
 
• If you are the parent/guardian of a child under the age of 18 who is being invited to participate in this 
study, the word “you” in this document refers to your child.  As the parent/guardian, you will be 
asked to read and sign this document to give permission for your child to participate.   
• If you are under the age of 18 and reading this document, the word “you” in this document refers to 
you.  You will be asked to read and sign this document to indicate your willingness to participate. 
 
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 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 scheduled to 
have spinal surgery and will receive anesthesia including drugs to reduce pain. 
 
Many different drugs are used in anesthesia and surgery including drugs to relieve pain. One commonly 
used drug is methadone. Methadone works quickly and lasts longer than other pain medications such as 
morphine. Methadone is approved by the U.S. Food and Drug Administration for treating pain in adults. 
Previous studies have shown that adults and adolescents are similar in how their bodies handle 
methadone used for pain during surgery. The purpose of this research study is to determine if 
administration of the drug methadone during surgery will reduce pain and reduce the amount of pain 
medications after surgery in adolescents and children.  A second purpose of this research study is to 
understand how well methadone controls pain, how long it last and how long it takes for children and 
adolescents to metabolize (get rid of) methadone from their bodies.  
 
WHAT WILL HAPPEN DURING THIS STUDY? 
If you and one of your parents decide for you to participate in this study your anesthesia will be exactly 
the same as if you were not in the study. In addition to other pain medication you may also receive a 
dose of methadone during your surgery. If you do not receive methadone you will receive other pain 


 
FOR IRB USE ONLY 
 
IRB ID #: 201302099 
APPROVAL DATE: 01/31/17 
RELEASED DATE: 02/03/17 
EXPIRATION DATE: 01/30/18 
 
Version 1.10.17 
 
Page 2 of 8 
medications such as morphine or dilaudid. 
 
 
This is a randomized study.  You will be randomly placed into 1 of 3 groups depending on when you are 
enrolled to the study.   
 
Study Cohorts:  If you are enrolled in one of the Methadone cohorts you will be randomized to receive a 
dose of methadone in the operating room.  The methadone dose will depend on your weight. 
 
Treatment Cohort: If you are enrolled in the methadone treatment cohort 1, you will be randomized to 
receive intravenous (IV) methadone HCI during your surgery.  
 
Control Cohort: If you are enrolled in the control cohort you will be randomized to receive a standard 
opioid pain medication, not methadone, by IV during surgery. 
 
This will be the only time you receive methadone for this study. 
 
Before your surgery and every morning for up to 6 days following the procedure (if you are still in the 
hospital), a member of the research team will ask you questions about your comfort level and any pain 
that you may experience. A numeric scale and pictures to depict how you are feeling will be used to help 
assess your comfort level and what you consider acceptable for treating any discomfort. You may be 
provided with an electronic tablet to answer questions about how you are feeling. Your parents will also 
be asked to use the tablet to answer questions about your overall wellbeing following your surgery. We 
also want to know if you experience side effects such as sleepiness, itching and nausea. 
 
To understand how long it takes methadone to disappear from the body, we need to draw blood several 
times after the methadone is given. We will take a total of about 3 tablespoons of blood over 4 days.  We 
will use the arterial line placed (routine standard of care) after you are asleep in the operating room to 
draw the blood for the first 24 hours. For the remaining samples, we will continue to collect a blood 
sample every morning for up to 4 days after your surgery from an IV (intravenous) catheter or collect 
samples with routine blood draws.  Your urine will be collected in a container that is provided for up to 
four days. Each day the research staff will provide a new container and will collect the container from 
the previous day. 
 
We will collect information from your medical record such as demographic data, pain medication use 
and information from your hospital stay. 
 
We would also like for you and your primary caregiver to complete a short questionnaire about your 
pain and its effects on your family before your surgery.  The questionnaire will take approximately 5 
minutes. 
 
Will you save my samples or research data to use in future research studies?  
As part of this study, we are obtaining blood samples from you. The samples we collect will be saved 
and labeled with a code and will not contain any personal identifiers, such as your name. If you agree, 
we would like to use your blood for other research projects going on now and in the future. These future 
studies may provide additional information that will be helpful in understanding pain. It is unlikely that 


 
FOR IRB USE ONLY 
 
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APPROVAL DATE: 01/31/17 
RELEASED DATE: 02/03/17 
EXPIRATION DATE: 01/30/18 
 
Version 1.10.17 
 
Page 3 of 8 
what we learn from these studies will have a direct benefit to you. By agreeing to be part of this study 
you give up any property rights you may have to these samples. There are no plans to provide financial 
compensation to you for allowing us to store your samples. Your blood samples may be used to develop 
investigational tests, treatments, drugs, or devices that are not yet approved by the U.S. Food and Drug 
Administration. 
 
I agree to have my blood stored:  Yes _______   
No  ______ 
 
 
 
 
 
initials  
       initials  
 
You will also be asked to have blood collected and used for genetic testing. The purpose is to obtain 
DNA (the blue print for a person’s genetic makeup) to help us learn about the genes (the part of DNA 
that tells your body how to make proteins) associated with pain.  We will look at the genes which may 
affect how long methadone lasts. Only personnel involved with this research project will have access to 
the DNA samples. You will not be told the results of the gene tests because they are experimental, and 
because we don’t know of any conclusive links between these genes and the risk of disease or any 
adverse events from drug therapy. If you agree, we will take approximately one teaspoon of blood either 
from your arterial line or from an IV at the same time as other blood sample collections. We will store 
your DNA for at least ten (10) years.  Your DNA will be given a code number and contain no personal 
identifiers. Your DNA samples may be used to develop investigational tests, treatments, drugs, or 
devices that are not yet approved by the U.S. Food and Drug Administration. 
 
I agree to have my DNA stored:  Yes ______           No  ______ 
 
 
 
 
 
initials  
      initials  
 
HOW MANY PEOPLE WILL PARTICIPATE? 
Approximately 75 people will take part in this study conducted by investigators at Washington 
University.   
 
HOW LONG WILL I BE IN THIS STUDY? 
If you agree to take part in this study, your involvement will last six days or until discharged from the 
hospital, whichever comes first. 
 
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. 
 
Methadone: 
The risks listed below can also happen with other pain medications. 
Likely:  Some people can get sick to their stomach (nausea) or throw up (vomit) after methadone.   
Less likely:  Methadone can possibly decrease your breathing rate, or cause sleepiness when several 
doses are given.  However these have not been a problem with the single dose we will give you, which 
has been used safely before.  
Rare:  Serious decreases in breathing rate or heart rate can happen in patients given many, very high 
doses for several days when first starting methadone.  You will receive only one dose.  


 
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APPROVAL DATE: 01/31/17 
RELEASED DATE: 02/03/17 
EXPIRATION DATE: 01/30/18 
 
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Completing the questionnaires or assessments may cause emotional discomfort, boredom, or fatigue. 
You have the right, however, to refuse to answer any question for any reason. 
 
All the information you give us will be given a code number. A master list linking the code number and 
your identity will be kept separate from the research data. Only the PI and people helping him/her will 
be able to see the list. We will protect your information, but there is a chance somebody might see it. 
 
Risk to the Unborn Child: 
Because the drugs in this study may affect an unborn baby, you should not become pregnant while in 
this study.  If you are a female capable of becoming pregnant, you must have a negative pregnancy test 
before beginning participation. This will be done as standard care. In addition, you must not be 
breastfeeding a baby during this study. 
 
Breach of Confidentiality:  
Medical records are considered confidential and records are kept in a secured area accessible only to the 
research team involved in the conduct of the study.  You will not be identified by name in any 
publication or presentation of the results of this study unless prior written consent is obtained.  Although 
we will make every effort possible to maintain confidentiality, there is however, a slight risk of breach 
of confidentiality. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
We don’t know if you will benefit from being in this study. 
 
However, we hope that in the future, other people might benefit from this study because we will have a 
better understanding of how methadone works in children and adolescents, which may improve the 
treatment of pain. 
 
WHAT OTHER TREATMENT OPTIONS ARE THERE? 
Before you decide whether or not to be in this study, your doctor will discuss the other options that are 
available to you.  If you do not want to participate in this study, the choice of pain medicine used for 
your surgery will be made by your anesthesiologist.  
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
You will not have any additional 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 not be paid for being in this research study.   
 
WHO IS FUNDING THIS STUDY? 
There is no funding for this study. 


 
FOR IRB USE ONLY 
 
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APPROVAL DATE: 01/31/17 
RELEASED DATE: 02/03/17 
EXPIRATION DATE: 01/30/18 
 
Version 1.10.17 
 
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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. 
Sharma at 314-454-4229 and/or the Human Research Protection Office at 1-(800)-438-0445.  
 
Decisions about 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.  
• Washington University’s Institutional Review Board (a committee that oversees the conduct of 
research involving human participants.) The Institutional Review Board has reviewed and 
approved this study.  
 
To help protect your confidentiality, we will have all paper documents locked office/filing cabinet of a 
member of the study team. We will keep all electronic documents on secured servers that are password 
protected and have various state of the art firewall protections with frequent upgrades of these 
protections. There is not an intention to transport the data; the only access point will be that of our 
secure research drives and servers. Of note, access to these electronic research files is restricted to only 
members of the study team. Your blood samples will be housed within the Department of 
Anesthesiology’s. 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. 
 
This consent form or similar documentation that you are participating in a research study will be 
included in your clinical medical record.  Anyone with access to your medical record, including your 
health insurance company will be able to see that you are participating in a research study. 
 
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. 
 
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 


 
FOR IRB USE ONLY 
 
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RELEASED DATE: 02/03/17 
EXPIRATION DATE: 01/30/18 
 
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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.  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 
• Your signature and this form will not expire as long as you wish to participate. 
• 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 if necessary for safety reasons.  
 You will not be allowed to continue to participate in the study. 
 
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.  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 


 
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APPROVAL DATE: 01/31/17 
RELEASED DATE: 02/03/17 
EXPIRATION DATE: 01/30/18 
 
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Page 7 of 8 
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 researchers might decide to end your participation in this research 
study earlier than planned.  This might happen 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: Lindsay Juriga, 314-454-7945. If you experience a research-related injury, please contact: Dr. 
Sharma at 314-454-4229. 
  
If you have questions, concerns, or complaints about your rights as a research participant, please contact 
the Human Research Protection Office, 660 South Euclid Avenue, Campus Box 8089, St. Louis, MO  
63110, 1-(800)-438-0445, or email hrpo@wusm.wustl.edu.   General information about being a research 
participant can be found by clicking “Participants” on the Human Research Protection Office web site, 
http://hrpo.wustl.edu.  To offer input about your experiences as a research subject 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. 
• 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. 
 
 
 
 
 
 
 
 


 
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APPROVAL DATE: 01/31/17 
RELEASED DATE: 02/03/17 
EXPIRATION DATE: 01/30/18 
 
Version 1.10.17 
 
Page 8 of 8 
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: 01/30/18. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Participant) 
 
 
 
 
(Date) 
 
 
____________________________________________ 
(Participant's name – printed) 
 
 
 
Parent/Guardian Name and Relationship to Participant: 
Do not sign this form if today’s date is after EXPIRATION DATE: 01/30/18. 
 
 
_______________________________ 
(Child’s name – printed) 
 
 
__________________________________________ 
_______________________________ 
(Signature of Parent/Guardian) 
 
 
 
(Date) 
 
 
__________________________________________ 
_______________________________ 
(Name of Parent/Guardian- printed)  
 
 
(Relationship to participant – 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)