Clinical trial NCT02278003
Conditions: Pediatric Pateints Amnesic Properties of Propofol
Keywords: Amnesic Propofol 12-006
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2012-02-01; Completion date: 2017-05-10
Enrollment: 69 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this study is to extend findings of propofol's effects on memory, as measured in volunteer research studies, to a clinical setting.

Detailed description:

Arms: arm 1: Children who will undergo sedation as part of their clinical management and give them a memory encoding task during propofol infusion to measure the effects of sedation. The mere task of naming a picture will encode that picture into memory. When the anesthesia has worn off (at approximately 1 hour later), children will be given a memory recognition task to measure the amnesic effects of propofol.

measure the amnesic effects of propofol. arm 2: A control group of children of similar age and undergoing similar minor therapeutic procedures will be recruited to perform memory.
Interventions: intervention 1: memory test intervention 2: Propofol
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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A Pilot Study to Assess the Amnesic Properties of Propofol in Pediatric Patients 
 
PROTOCOL FACE PAGE FOR  
MSKCC NON THERAPEUTIC PROTOCOL 
 
Principal Investigator/Department: 
Eric Kelhoffer, MD     
 
Anesthesiology/Critical Care 
Co-Principal Investigator(s)/Department: 
Robert A. Veselis, MD     
Anesthesiology/Critical Care 
Investigator(s)/Department: 
Kara Barnett, MD 
Luis Tollinche, MD  
Cindy Yeoh, MD 
Jennifer Mascarenhas, MD 
Vittoria Carlon, MD 
Jamie Fortunoff, MD 
Leslie Ojea, MD 
Michael Long 
Michelle Sckolnick, MD 
Hallie Weiss, MD 
Alan Kotin, MD 
Anahita Dabo-Trubelja 
Larisa Storozhenko 
Anoushka Afonso, MD 
Meghana Mehta 
Yuelin Li, PhD  
Kim Kramer, MD  
Shakeel Modak, MD 
Jane Song 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Epidemiology/Biostatistics 
Pediatrics 
Pediatrics 
Graduate Medical Education 
Consenting Professional(s)/Department: 
Eric Kelhoffer, MD  
Robert A. Veselis,MD  
Kara Barnett, MD 
Luis Tollinche, MD  
Cindy Yeoh, MD 
Jennifer Mascarenhas, MD 
Vittoria Carlon, MD 
Jamie Fortunoff, MD 
Leslie Ojea, MD 
Hallie Weiss, MD 
Alan Kotin, MD 
Anahita Dabo-Trubelja 
Larisa Storozhenko 
Anoushka Afonso, MD 
Michael Long 
Michelle Sckolnick, MD 
Fernando Panchana 
Meghana Mehta 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 
Anesthesiology/Critical Care 


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Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065


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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA..................................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 4 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ......................................................... 10 
4.1 
Design .......................................................................................................................... 10 
4.2 
Intervention ................................................................................................................... 10 
5.0 
CRITERIA FOR SUBJECT ELIGIBILITY ......................................................................... 11 
5.1 
Subject Inclusion Criteria .............................................................................................. 11 
5.2 
Subject Exclusion Criteria ............................................................................................. 11 
6.0 
RECRUITMENT PLAN ..................................................................................................... 11 
7.0 
ASSESSMENT/EVALUATION PLAN .............................................................................. 11 
8.0 
TOXICITIES/SIDE EFFECTS ........................................................................................... 12 
9.0 
PRIMARY OUTCOMES ................................................................................................... 12 
10.0 CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 12 
11.0 BIOSTATISTICS .............................................................................................................. 13 
12.0  RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES
 
16 
12.1 Research Participant Registration ................................................................................. 16 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. ........ 16 
12.2 Randomization .............................................................................................................. 16 
13.0 DATA MANAGEMENT ISSUES....................................................................................... 16 
13.1 Quality Assurance ......................................................................................................... 16 
13.2 Data and Safety Monitoring ........................................................................................... 17 
14.0 PROTECTION OF HUMAN SUBJECTS .......................................................................... 17 
14.1 Privacy .......................................................................................................................... 18 
14.2 Serious Adverse Event (SAE) Reporting ....................................................................... 18 
14.2.1 ................................................................................................................................... 19 
15.0 INFORMED CONSENT PROCEDURES .......................................................................... 19 
16.0 REFERENCES ................................................................................................................. 20 
17.0 APPENDICES .................................................................................................................. 21 
 
 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
The goal of this study is to extend findings of propofol’s effects on memory, as measured 
in volunteer research studies, to a clinical setting. Standard memory tasks utilized in 
clinical drug studies do not readily differentiate between effects on memory from 
sleepiness alone (sedation) or from a specific effect of certain drugs (e.g. 
benzodiazepines, propofol) on memory itself (amnesia). We have been able to 
differentiate these effects in adult volunteers using a visual picture task where intravenous 
infusion produced increasing drug concentrations over a period of approximately 10 
minutes. We wish to assess the feasibility of using this behavioral paradigm in a clinical 
setting.  
Very little research on the immediate memory effects of anesthetic drugs in pediatric 
patients has been done, as many tasks that test memory function are not suitable for 
pediatric patients, particularly in a busy clinical setting. The visual picture task used in our 
volunteer studies, on the other hand, is simple in nature and should be able to be 
performed easily by younger patients with minor disruption in procedure traffic.  
We wish to assess the feasibility of a similar picture naming task in pediatric patients who 
require sedation for minor therapeutic procedures, principally MRI scans of the brain.  
Pediatric patients who are old enough to be able to name pictures will be offered inclusion 
in the study. Before the therapeutic procedure is begun, during induction of sedation, 
pictures will be shown to the child while they name them. This procedure will form 
memories as propofol concentration is increasing. After awakening following completion of 
the therapeutic procedure, recognition memory will be tested for the pictures presented as 
propofol sedation was being induced.  
A control group of children of similar age and undergoing similar minor therapeutic 
procedures will be recruited to perform memory tasks as for the children who receive 
propofol. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
1. The primary objective is to determine the feasibility of using the visual picture naming 
task in pediatric patients in the clinical setting. Feasibility will be defined as being able to 
accrue an average of 2 patients a week who successfully name and recognize sufficient 
numbers of pictures so that the thresholds for sedation and memory can be determined in 
each individual (as described in Section 11.0, Aim 1). 
2. The strength of propofol amnesia (the effect of propofol on memory not related to 
sedation) will be estimated as a difference between thresholds for amnesia (loss of 
memory) and sedation (loss of verbal responsiveness) 
 
 


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Hypothesis 1: The threshold effect for memory will occur significantly sooner, i.e. at lower 
drug concentrations, than the threshold effect for sedation, as illustrated in Fig 2 (the 
threshold for memory effect is illustrated by the light gray curves in the Figures, and for 
sedation by the dark curves). 
3.0 
BACKGROUND AND RATIONALE 
Amnesia versus Sedation 
One of the critical components of anesthesia is amnesia (lack of recall) for events during 
surgery or therapeutic procedures. The failure of this anesthetic effect, i.e. conscious 
awareness and recall of events during anesthesia, known as ‘awareness’, occurs at a low, 
but predictable frequency of ~0.5% both in adults and children. (1) In fact, the incidence of 
this complication may be higher in the pediatric population. (2) (3) Serious psychological 
sequelae may occur after an episode of awareness, with symptoms similar to those of 
post-traumatic stress disorder. (4) (5) (6) This eventuality may be particularly distressing 
for patients with cancer, who frequently require repeated therapeutic procedures. The fact 
that the incidence of awareness is so low makes it difficult to conduct systematic studies to 
address this issue. Thus, practice aimed at prevention of this complication is frequently 
based on expert opinion. One common recommendation is to use drugs with specific 
amnesic properties during anesthesia.  
A more precise definition of an amnesic drug is one that is able to prevent recollection of 
memories at low or minimal levels of sedation. Amnesic drugs are useful adjuncts to other 
anesthetic agents, most of which prevent recall of intra-operative events on the basis of 
sedation alone, i.e. no conscious memories are formed because the patient is unable to 
experience and process stimuli from the outside world. However, periods of inadequate 
anesthetic level may occur for any number of reasons e.g. individual response to 
medications, sudden painful stimulus, hemodynamic instability necessitating decreased 
drug doses, refilling the drug delivery device, ‘stormy’ induction or emergence, etc. The 
rationale for the routine use of an amnesic drug is that it will prevent recall of any events 
occurring during periods of inadvertently light anesthesia. Midazolam is such an amnesic 
drug, and is frequently used in the therapeutic setting for this reason. Relative 
disadvantages of midazolam include relatively prolonged duration of action, of particular 
concern in the outpatient setting, and the inability to act as a suitable anesthetic agent 
when given alone. Propofol has been shown in many studies in adults to possess specific 
amnesic properties, both in the research and clinical settings. (7) (8) (9) (10)  To date, 
propofol provides the most desirable qualities for an ‘all-purpose’ anesthetic agent, as it 
possesses amnesic properties, has a short duration of action, and can be administered as 
the sole anesthetic agent. 
Sedation for therapeutic procedures in children 
As propofol has desirable pharmacokinetic properties that allow deep levels of sedation 
commensurate with rapid recovery, it is the most common sedative agent given to 
pediatric patients for therapeutic procedures. However, almost no research has been done 
to determine if propofol is indeed an amnesic, as opposed to a purely sedative drug when 


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given to pediatric patients. (11) There is evidence that the pharmacodynamics for propofol 
are different in children than adults, so the amnesic effects present in adults need to be 
confirmed in children. (12) Recently dexmedetomidine, an agent with a similarly favorable 
pharmacologic profile to that of propofol, has been introduced for sedation in pediatric 
patients. (13,14) Similarly to propofol, there is no research in pediatric patients regarding 
the memory effects of dexmedetomidine. In adult patients, the amnesic effect of 
dexmedetomidine is unclear, but there are some data to indicate that dexmedetomidine 
has few amnesic properties. (15) (16) (17) Interestingly, when dexmedetomidine was used 
for sedation in pediatric patients, improvement in the quality of sedation was noted when a 
known amnesic agent (e.g. midazolam or ketamine) was co-administered. (18,19) 
Whether this improvement may have been a result of the additional amnesic effect of 
these drugs, or some other property is unknown. 
Thus, the possibility exists that using agents with amnesic properties may provide better 
quality of sedation in pediatric patients. The only way this hypothesis can be critically 
assessed is to have some measure of the amnesic effect of a given drug when given to 
pediatric patients in a clinical setting.  
Measures of amnesic versus sedative effects 
Sedative effects of anesthetic drugs can be measured in real time, for example by 
assessing reaction time, or presence of an adequate behavioral response while the drug is 
being given (e.g. keeping eyes open, or performing a simple task such as naming a 
picture). However, the assessment of memory is by definition retrospective. The memory 
effect of amnesic drugs develops over 10-30 minutes, and the full extent of memory 
impairment is only evident after this time interval has elapsed. (7,16) Measures of memory 
impairment due to a drug use recognition performance at some distinct time after the 
sedative effect of a drug was measured during administration. Thus, comparison of the 
amnesic and sedative properties of a drug represent behavioral responses obtained at two 
distinct time points. Modulation of the memory effect of a drug is related back in time to 
conditions present when the memory was being formed, i.e. at encoding. For the purposes 
of this study we are assessing modulation of memory by the degree of sedation present at 
encoding. (20) (21) 
The methods used to assess the amnesic properties of drugs in the clinical setting are 
quite limited in comparison to controlled research settings. (22) Frequently measures of 
memory are used which cannot differentiate among the various factors that impair memory 
in the clinical setting. For example, anxiety in the peri-operative setting can itself impair 
memory for events before the administration of anesthesia. (23) Other difficulties in 
translation of methods to the clinical setting include the use of other drugs, timing of 
measurements, the presence of painful treatments, etc. (24) One of most difficult issues to 
address is the ability to separate the amnesic and sedative effects of drugs on memory. 
(25) (21) A behavioral paradigm that could separate sedative and amnesic effects of drugs 
easily applied in the clinical setting would allow the ability to measure the influence of the 
amnesic properties of a given drug on outcome, for example patient satisfaction with 
anesthesia or recall of procedure events. Over the past decade we have developed 


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methods to measure amnesic versus sedative effects, in particular with propofol, in the 
research setting using volunteers. (7,16,21)  
The drug ramping paradigm 
A simple paradigm that allows amnesia to be differentiated from sedation is to infuse drug 
in increasing concentrations over a period of ~10 minutes. During this time period, as drug 
concentration and sedation are increasing, visual stimuli are presented. Importantly, these 
stimuli are attended to by performance of a task, in this case by naming a picture. A 
positive response on the task, naming the picture either correctly or incorrectly, confirms 
that the stimulus was processed sufficiently to be learned and allow testing for subsequent 
recognition.  
The full range of sedation effects is achieved by administering the drug at a rate so that no 
sedation is present initially, with levels of sedation present that allow the naming task to be 
performed  during the bulk of the infusion period. By the end of the infusion period 
sedation appropriate for the therapeutic procedure is present, namely, unresponsiveness 
to voice. Analysis of subsequent recognition memory and sedation at the time of encoding 
allows one to determine the time of picture presentation at which 50% memory effect 
occurs and compare it  to the time at which 50% sedation occurs. The larger the 
separation between these two dose-response points, the greater are the amnesic 
properties present for the drug. This is illustrated below using exemplars from volunteer 
studies we have previously conducted. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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FIG 1 Infusion of a typical sedative drug (thiopental) over 10 minutes, during which time 60 pictures 
were shown. As time increased (higher picture number), sedation increased, and fewer responses 
occurred (dark dots). Response data (response to picture task during infusion (yes/no) and subsequent 
recognition of picture, gray crosses) were fitted to regression curves. For sedative drugs, the 
subsequent lack of recognition memory parallels the increase in sedation, i.e. there was no specific 
amnesic effect (a small difference in 50% effect (horizontal black line) for memory and sedation)


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FIG 2 Infusion of propofol (a typical amnesic drug) over 10 minutes, during which time 60 pictures 
were shown. As time increased (higher picture number), sedation increased only at the end of infusion 
(dark line). The hallmark of amnesia is the lack of subsequent recognition which begins well before any 
increase in sedation (dark line, a large difference in 50% effect for memory and sedation).
 
As there is substantial evidence that propofol is amnesic in adults and propofol is the most 
common sedative agent used for pediatric procedures, we wish to initially test the drug 
ramping paradigm as a measure of amnesic effect using propofol in pediatric patients. The 
main goal of this study is to determine the feasibility of patient accrual and ability to define 
the relationship of amnesia to the level of sedation.  
In summary, a rationale exists, but is not proven, for the desirability of specific amnesic 
properties for drugs used during sedation/anesthesia. The development of an instrument 
to detect the amnesic effect of a given drug in a clinical setting would not only confirm 
results from previous volunteer studies, but would provide an opportunity to measure an 
important variable in patient outcome in terms of recall of the surgical/therapeutic 
experience, or of patient satisfaction. If the quality of amnesia does indeed relate to 
outcome, then this measure applied in the clinical setting would provide a rational basis for 
drug selection. Future studies could be used to compare drugs with similar 
pharmacokinetic profiles, for example, propofol with dexmedetomidine or various 
inhalational agents.  
A protocol using the same methodology as in the current one is now open at Boston 
Children’s Hospital, where dexmedetomidine is used for pediatric sedation. Accrual 
demographics are nearly identical with the patients accrued so far to the MSKCC protocol. 
Inclusion of a control group at both sites will validate a more direct comparison of memory 
effects from propofol with those of dexmedetomidine. 


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Post-Operative Cognitive Dysfunction 
Another important clinical issue is the presence of cognitive dysfunction after anesthesia in 
the elderly with impaired cognitive reserve. (26-28) (29,30) Memory impairment is an 
important component of post-operative cognitive dysfunction, which in turn is associated 
with a higher incidence of post-operative delirium, and poorer outcomes. (31) Of 
importance, patients of all ages who have received chemotherapy demonstrate varying 
degrees of cognitive impairment. (32) Thus, in theory, this patient population may be at 
similar risk to elderly patients with diminished cognitive reserve in terms of post-operative 
cognitive dysfunction. In fact, age, cognitive reserve and chemotherapy are all important 
determinants of cognitive performance. (33) If feasibility is demonstrated in the current 
protocol, the proposed behavioral paradigm could then be tested in a more heterogenous 
adult patient population. The drug ramping paradigm could be a useful tool to assess the 
sensitivity of different patient populations to acute memory impairment by drug 
administration. The paradigm could be easily modified to assess memory function at 
various time points before and after intervention (as we have done to define memory 
decay characteristics in volunteers after receiving sedative and amnesic agents (16)). 
Substantial improvement in patient outcome may be possible if anesthetic management 
could be modified to decrease the incidence of POCD or delirium. Development of a 
behavioral measure of amnesia / memory dysfunction that can be easily applied in the 
clinical setting is a key component of this process.  
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
Children either requiring sedation or not for therapeutic or diagnostic procedures will be 
offered inclusion in the study. Sedation will be induced over a period of 10 minutes by 
administering propofol at an infusion rate that will produce suitable conditions for the 
procedure at the end of infusion (heavily sedated or asleep). During the infusion pictures 
will be shown to the child who will be encouraged to name the item in the picture. After 
completion of the procedure, when the child is awake and being assessed for discharge, 
memory will be tested using forced choice recognition of pictures previously shown 
intermixed with novel pictures. The child will indicate yes/no whether the picture was seen 
during induction of sedation. Children not requiring sedation will perform exactly the same 
tasks as described above, but without any drug infusion. 
4.2 
Intervention 
During induction of sedation, or in the case of no sedation, before the therapeutic 
procedure, children will be encouraged to name the items shown in pictures displayed, 
one every 5 seconds, as drug concentration is increasing. Naming pictures will ensure that 
items are being attended to and memory systems are engaged. The child’s response will 
be used to assess the degree of sedation present (response present / response absent). 
After recovery from sedation, or after a similar time period after the therapeutic procedure 


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(approximately 40 min) for children in the control group memory for the previously 
presented pictures will be tested using a yes/no response. The recognition testing set will 
contain both previously seen and novel items. 
5.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
Describe the characteristics of the subject population. 
5.1 
Subject Inclusion Criteria 
• 
The patient must be between 4 and 14 yrs of age and be undergoing a therapeutic 
or diagnostic procedure with or without sedation 
• 
The patient must be able to comprehend and perform the task (naming pictures) 
• 
The patient must have a minimum weight of 8 kg   
5.2 
Subject Exclusion Criteria 
• 
Allergy to propofol (for those patients requiring sedation) 
• 
Procedure of short duration (< 15 min)  
• 
Pregnancy 
• 
Recent use (within 5 half-lives) of centrally acting medications that could affect 
concentration (e.g. diphenhydramine) 
6.0 
RECRUITMENT PLAN 
Pediatric patients undergoing therapeutic or diagnostic procedures that might require 
sedation will be offered inclusion in the study on the day of the procedure upon arrival to 
the Pediatric Day Hospital. It is anticipated that between 2 and up to 5 patients a week will 
participate in this study. 
7.0 
ASSESSMENT/EVALUATION PLAN 
The recognition memory task will consist of simple line drawings selected from a larger stimulus 
data base (http://crl.ucsd.edu/experiments/ipnp/method/getpics/getpics.html) based on their age 
appropriateness and identifiability by children in the target age range. Stimulus items are 
presented by means of a bound stimulus book with one black and white line drawing presented 
on each page. A brief test will be performed to familiarize the child with performing the picture 
naming task, using different pictures from those that will be shown in the study. If the child is not 
able to cooperate sufficiently with the test task, then he/she will be withdrawn from the study and 
propofol will then be administered as per normal clinical practice for their procedure. If sedation 
will be needed, propofol infusion will be started at a rate to deliver 3mg/kg over a 10 minute 
period. During this learning phase of the study, pictures will be presented to the participant and 
the participant will be asked to name each object pictured with accuracy and non responses will 
be recorded by the examiner. If sedation is being given, the drug infusion rate will be adjusted 
according to clinical observation (e.g. excessive sedation/no drug effect apparent) so that the 
patient will be appropriately sedated for the planned procedure by the end of the 10 minute 
infusion period. After conclusion of the initial infusion, propofol will be administered as per usual 
practice. Following the procedure after awakening in the PACU, when no apparent sedation is 


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present, or after a similar time period, if no sedation was used, the picture recognition phase of 
the study will be performed. Patients will again be presented the original pictures with an equal 
number of pictures not seen during the infusion phase. The order of pictures in the learning 
(propofol infusion) and recognition phases(PACU) will be the same for every patient. The child will 
indicate whether the picture was seen before (yes/no). The study is complete. The child will be 
discharged form the PACU as per standard clinical criteria.”  
8.0 
TOXICITIES/SIDE EFFECTS 
As is normally used for pediatric sedation, propofol will be used. As the length of sedation 
for the procedure is anticipated to be more than a few minutes, propofol will be infused 
using a drug infusion pump, as is routinely done now. Thus, no additional toxicities/side 
effects beyond those associated with the clinical administration of propofol as currently 
practiced are present. 
9.0 
PRIMARY OUTCOMES 
Several factors affect the feasibility of the proposed study design, including 1) accrual rate 
in the proposed 4 – 6 months study period, 2) drop-out rate (children who complete the 
picture naming task during infusion but fail to complete the memory task post recovery), 
and 3) sufficient data (e.g., few observations during the picture naming task because the 
child falls asleep quickly; few accurate responses during the memory task).   
The accrual and dropout rates will be addressed by keeping a running tally of the number 
of recruited participants to monitor the recruitment numbers.  Our target is to recruit at 
least an average of 2 out of the anticipated 4 – 6 children per week.  However, it would be 
impractical to set a fixed recruitment target for a pilot study of this nature.   
Factors associated with data sufficiency will have to be determined after the data have 
been collected.  For example, we have to wait until the data have been collected before 
we can begin calculating the proposed threshold statistic (Section 14 below).  The 
statistical computer packages may or may not be able to derive a stable estimate of the 
threshold measure per child.  This will have to be determined after each child’s data have 
been collected, entered, and fitted for the threshold statistics. 
It is premature to anticipate a statistically reliable difference between the two threshold 
measures, one for the sedative effect threshold and the other for the memory effect 
threshold.  These will have to be ascertained after the data have been collected, entered, 
fitted, and plotted in the manner similar to Figures 1 and 2 above.  It is plausible that the 
threshold values are similar in some children and quite different in some other children.  
An important goal of this study is to examine the variability between the two threshold 
values among the sample of children.   
10.0 CRITERIA FOR REMOVAL FROM STUDY 
If the patient cannot adequately perform the picture naming task (defined as verbally 
responding to >80% of the pictures presented before falling asleep, or half way through 
the list in the case of no sedation) through a significant portion of the initial 10 minute 


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infusion, data collection will be stopped, the patient withdrawn from the study, and no 
further testing be performed. Similarly, if the patient is unable or unwilling to perform the 
recognition task, he/she will be withdrawn from the study. In the extremely unusual 
circumstance of severe or unanticipated toxicity from the administration of propofol (e.g. 
allergic reaction), the participant will be withdrawn from the study. Any participant who is 
removed from the study prior to the start of their procedure for reasons other than toxiticity 
(i.e., inability or unwillingness to complete the practice or actual task) will then be 
administered propofol as per normal clinical practice for their procedure. 
11.0 
BIOSTATISTICS 
Overview.  This study is a pilot project to separately examine the amnesic and the 
sedative effects of the drug propofol.  The plan is to recruit a pilot sample of 40 children 
who will undergo sedation as part of their clinical management and give them a memory 
encoding task during propofol infusion to measure the effects of sedation.  The mere task 
of naming a picture will encode that picture into memory. When the anesthesia has worn 
off (at approximately 1 hour later), children will be given a memory recognition task to 
measure the amnesic effects of propofol. We will also recruit a total of 30 children who will 
not undergo sedation to serve as a control group. This brings out total number of 
participants to 70. 
Analytic Plans for the Specific Aims: 
Aim 1:  The primary objective is to determine the feasibility of using the visual picture 
naming task in pediatric patients in the clinical setting. Feasibility will be defined as, at the 
conclusion of the study, 25 or more of the pilot sample of 30 (control) or 35 (propofol) per 
group complete the recognition memory task and yield usable parameter estimates for the 
psychophysics function.  The probability of declaring the study design feasible is 0.51 
when the true population feasibility is 0.70; and the probability of a feasible study 
increases to 0.92 when the true population feasibility is 0.80. 
Descriptive statistics will be sought to examine study feasibility.  A running tally of the 
number of recruited participants will be kept to monitor the recruitment numbers during the 
anticipated 4 – 6 months study period.  Due to the complex nature of this research, many 
factors affect study feasibility.  It would be impractical and unrealistic to set an a priori 
feasibility target.  Rather, we will monitor several factors, including patient volume, rate of 
study consent, the proportion of patients who can complete the experimental tasks and the 
practicality of fitting the psychophysical Weibul model described below.  Study feasibility 
will be evaluated holistically at the end of the study by the study investigators. 
 
As for the minimally sufficient number of responses, the 10-events-per-parameter rule of 
thumb may apply here. (34)  Although that rule was developed for logistic regression, 
which may or may not be too restrictive for the SAS NLMIXED procedure we intend to use 
to fit the threshold functions. 
 


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Aim 2.  Illustrative Examples.  Aim 2 involves the calculation of a “sedation threshold” 
and a “memory threshold” for each child.  Figures 1, and 2 provide illustrative examples on 
how the separate sedative and amnesic effects will be estimated statistically.  An example 
is provided below to explain the procedures and the analytic plan. 
1. “Sedation threshold”: During the 10-minute infusion of propofol, children will be 
presented with pictures at 5-second intervals and asked to name the picture.  They will be 
asked to name each picture (e.g., cat, tree, pencil, etc.). A valid response is naming of the 
picture within 5 seconds, either correctly or incorrectly.The important response measure is 
whether the child is awake enough to perform the naming task. Though the picture list is a 
validated set of stimuli, as described in Section 7.0, some stimuli may end up being too 
difficult to name for children of this age group. Thus no response due to sedation may be 
confounded by no response due to an inappropriately difficult stimulus. Responses from 
the control group of children will be used to eliminate problematic stimuli which reach a 
given criterion of no response at both sites. 
In Figures 1 and 2, the dark circles with a value of 1 on the y-axis represent that the 
participant is making valid responses.  The dark circles with a value of 0 on the y-axis 
represent lack of a valid response because the participant is sedated to the point of 
impaired response performance as propofol concentration continues to increase.  As the 
child gets sedated and becomes gradually sleepier as the infusion continues, he/she is 
less likely to make a valid response (thus the increased frequency of dark circles at the 
bottom of the Figures as image number increases).  The dark line in Figure 1 represents 
the estimated sedative effects over time.   
There is a vast literature in psychophysics on modeling the shapes of these curves.  Since 
the seminal paper by Quick (1974; Kybernetik, 16: 65-67: PMID: 4453110), the model 
below has been used extensively in modeling various psychophysical functions. We will 
use an asymmetric Weibull cumulative density function F(x) to model in the overall 
probability of a valid response G(x) over time x:  
𝐺(𝑥) = 0.5 + 0.5 ∙𝐹(𝑥) 
                          = 0.5 + 0.5 ቂ1 −e−(α∙x)βቃ, 
where α > 0 and β > 0 are the scale and shape parameters, respectively, and x ≥ 0. (35)  
The constant of 0.5 assumes a 50-50 chance of a random response in a psychophysical 
task.  Conventionally, the median of F(x) is called the “threshold” of the underlying 
psychometric function (the value of x for which F(x) = 0.5).  Because of the assumed 0.50 
constant in G(x), and the 0.5 times the median of the Weibull, the threshold estimate is the 
x value of an overall 75% response probability given the Weibull parameters. The 
threshold of a psychometric function generally represents the strength of stimulus that 
elicits a sensation or a noticeable difference.  In this case the sedation threshold 
represents the time value of x when sedation is actuated.  We will estimate one sedation 
curve and its corresponding threshold for each child. 


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2. “Memory threshold”: When the anesthesia has worn off at approximately 1 hour later, 
the child will be presented with another list of 120 pictures with half having been presented 
during the initial infusion of propofol.  At the presentation of each picture, the child will be 
asked whether or not he/she remembers having seen it previously.  Each response will be 
coded as correct (true positives and true negatives) or incorrect (false positives and false 
negatives).  A curve may be fitted to the memory recognition data to estimate the average 
memory decay function for each child.  In Figure 1 and 2 this is represented as the light 
gray curve, which can be modeled as 1 – G(x) above.  Similarly, a threshold represents 
the time value (picture number) when memory fades below threshold. 
The sedation threshold in Figure 1 is at image 25 (250 seconds), while the memory 
threshold is at approximately image 28 (280 seconds).  This 30-second / 3 picture 
difference is taken to represent that sedation occurs concurrently with memory decay.  
Alternatively, in Figure 2, the sedation threshold is at image 58 (580 seconds) while the 
memory threshold is approximately at image 40 (400 seconds).This larger difference of 
180 seconds / 18 pictures is a measure of how much sooner amnesia occurred in this 
instance than sedation. In this latter case, a measureable amnesic effect of 180 seconds 
can be inferred from the two threshold values.  
Calculations of the sedation and memory thresholds.  The overall statistical paradigm will 
involve non-linear regression modeling to estimate G(x) functions for the memory and 
sedation curves for each child in order to address the main hypothesis:  
“The threshold effect for memory will occur significantly sooner, i.e. at lower drug 
concentrations, than the threshold effect for sedation”. 
Sample Size Considerations.  The proposed pilot sample of 35 children accrued to the 
propofol group is primarily determined by our plan to complete the study within 4-6 
months.  In our experience we have a pool of approximately 10 children who undergo 
anesthesia for clinical scans each week who would meet the eligibility criteria.  Among 
them an anticipated 50% would agree to participate in this study.  If half of these (2-
3/week) produce data of sufficient quality to be able to perform curve fitting as described 
above, we expect to complete recruitment within 5 months. 
A sample of 35 children will also yield an 80% power in a one-sample t-test against the 
null that the difference in the sedation and memory thresholds is zero (null ~ N(0, 1)), 
assuming a two-sided Type-I error rate of 0.05, and an alternative population distribution 
with a mean of 0.50 and a standard deviation of 1.0.  The statistical power was estimated 
by the G*Power computer program. 
 
 
 
 


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12.0 
 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
12.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. The PPR fax numbers are (646) 735-0008 
and (646) 735-0003. Registrations can be phoned in or faxed. The completed signature 
page of the written consent/verbal script and a completed Eligibility Checklist must be 
faxed to PPR. 
12.2 
Randomization 
This study does not require randomization. 
13.0 
DATA MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of 
the RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinating the activities 
of the protocol study team. The data collected for this study will be entered into a secure 
database. Source documentation will be available to support the computerized patient 
record. All data will be maintained by the RSA under the direct supervision of the principal 
investigator. 
13.1 
Quality Assurance
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to assess 
missing data and inconsistencies. Accrual rates and extent and accuracy of evaluations 
and follow-up will be monitored periodically throughout the study period and potential 
problems will be brought to the attention of the study team for discussion and action 
Random-sample data quality and protocol compliance audits will be conducted by the 
study team, at a minimum of two times per year, more frequently if indicated.  
 
 
 


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13.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Essential Elements of a Data 
Safety and Monitoring Plan for Clinical Trials Funded by the NCI” which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines. The DSM Plans at MSKCC 
were established and are monitored by the Office of Clinical Research. The MSKCC Data 
and Safety Monitoring Plans can be found on the MSKCC Intranet at:  
http://mskweb5.mskcc.org/intranet/_assets/_tables/content/359709/DSMPlans07.pdf.   
There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality. There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and 
staff education on clinical research QA) and departmental procedures for quality control, 
plus there are two institutional committees that are responsible for monitoring the activities 
of our clinical trials programs. The committees: Data and Safety Monitoring Committee 
(DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring Board 
(DSMB) for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. During the protocol development and review process, each 
protocol will be assessed for its level of risk and degree of monitoring required. Every type 
of protocol (e.g., NIH sponsored, in-house sponsored, industrial sponsored, NCI 
cooperative group, etc.) Will be addressed and the monitoring procedures will be 
established at the time of protocol activation. 
14.0 
PROTECTION OF HUMAN SUBJECTS 
As is routinely performed, a medical doctor will be present during drug administration and 
performance of the therapeutic procedure (usually MR scanning) and vital signs will be 
monitored by clinical monitoring equipment. After sedation is established, propofol dosing 
will be adjusted as per clinical routine during the therapeutic procedure. Each patient will 
be observed for as long as necessary after the conclusion of the procedure, and will meet 
the usual clinical discharge criteria used for ambulatory surgery.  
Side effects of sedative agents are more pronounced with bolus administration than 
continuous infusion. Using a continuous infusion to obtain targeted concentrations will 
minimize the potential side effects of propofol.  
No direct benefit to the participant is expected from participation in the study and 
participants will not be reimbursed for participation in the study.  
All members of the research study team will have current certification in HIPAA 
Regulations and Human Subjects Protection as required by the NIH. Every effort will be 
made to ensure that this study is conducted within the federal, state, local and institutional 
guidelines regarding research involving the use of human subjects. To this end, the 
following will be done: 


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The potential risks including adverse drug reactions will be discussed in detail with 
patients. No patient will be required to participate in the study and participation or lack of 
participation will not affect the patient's subsequent care or treatment.  
The patient will not incur any financial cost as a result of participation in the study.  
Throughout the study, patient confidentiality will be maintained. No results of the study will 
be presented or discussed in a fashion that will allow identification of a particular patient in 
the study. Any protected health information used for the study will be maintained in a 
secure drive (as described in Section 13.0) and handled only by those individuals 
authorized by the patient to do so as indicated by their signature on the Research 
Authorization (as described in Section 15.0).  
All adverse events will be fully disclosed to the MSKCC IRB in a timely fashion as 
required. SAE reporting procedures will be carried out as described in Section 14.2. 
Participation will be purely voluntary and informed consent will be obtained for all patients 
who choose to participate in the study. This informed consent process will be documented 
as described in Section 15.0. 
14.1 
Privacy 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure 
of protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB).  
14.2 
Serious Adverse Event (SAE) Reporting 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be 
submitted electronically to the SAE Office at sae@mskcc.org.  The report should contain 
the following information: 
Fields populated from CRDB: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of     
      MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 


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• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report.  
We expect that our patients may be hospitalized in relation to their cancer. However, due 
to the nature of our non-therapeutic study, we will not report hospitalizations or any other 
events unrelated to the procedures outlined in our protocol as SAEs. 
14.2.1  
N/A 
15.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that they 
are free to withdraw from the study at any time. All participants must sign an IRB/PB-
approved consent form indicating their consent to participate. This consent form meets the 
requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following:  
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time.  
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
 


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16.0 
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17.0 
APPENDICES 
Appendix 1. Gallery of images to be shown to protocol participants