Dose Response Relationship of Dexmedetomidine in Decreasing Post Operative Analgesic Requirements in the Pediatric Tonsillectomy Patient
Phase: PHASE4
Conditions: Pediatric Adenotonsillectomy, Post Operative Analgesia
Sponsor: Baylor College of Medicine

Identifiers: NCT01057381
Unique Protocol ID: H-17558
Title: Dexmedetomidine in Pediatric Tonsillectomy
Date: 3 June 2005

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Institutional Review Board for Baylor College of Medicine and Affiliated
Hospitals
 
Protocol Number:    H-17558
Status:                        Closed
Initial Submit Date:  6/3/2005
 
Section Aa:  Title & PI
A1.  Main Title
     DOSE RESPONSE RELATIONSHIP OF DEXMEDETOMIDINE IN DECREASING POSTOPERATIVE ANALGESIC
REQUIREMENTS IN THE PEDIATRIC TONSILLECTOMY PATIENT.
A2.  Principal Investigator
 
     Name:  
OLUTOYIN OLUTOYE
Phone:  
832-824-5800
     Id:  
136354
Fax:  
832-825-5801
     Department:  TCH BASED PROGRAMS
Email:   
oao@bcm.tmc.edu
     Center:  
Mail Stn:  SM1003
A3.  Administrative Contact
 
     Name:
BARBARA S SKJONSBY
Phone:  
832-824-5800
     Id:  
021999
Fax:  
     
Email:   
skjonsby@bcm.tmc.edu
     
Mail Stn:  BCM320
A3b.  Cooperative Agreement
     Is this a cooperative agreement protocol?
          No
     Which institution is the IRB of record?
          BCM: Baylor College of Medicine
 
Section Ab:  General Information    
A4.  Co-Investigators
 
     Name:  
DANIEL E GRAVES
Phone:  
713-799-5023
Id:  
035186
Fax:  
713-799-5030
Department:  PHYSICAL MEDICINE & REHABILITATION
Email:   
dgraves@bcm.tmc.edu
Center:  
Mail Stn:  TIRR
 
     Name:  
TAE W KIM
Phone:  
832-824-5800
Id:  
043600
Fax:  
832-825-5801
Department:  TCH BASED PROGRAMS
Email:   
twkim@bcm.tmc.edu
Center:  
Mail Stn:  BCM320
 
     Name:  
MEHERNOOR WATCHA
Phone:  
832-824-5800
Id:  
157663
Fax:  
Department:  TCH ANESTHESIOLOGY
Email:   
watcha@bcm.tmc.edu
Center:  
Mail Stn:  BCM320
 
     Name:  
CHRIS GLOVER
Phone:  
832-824-5802
Id:  
691844
Fax:  
832-825-5801

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Department:  ANESTHESIOLOGY: BCM
Email:   
cg691844@bcm.tmc.edu
Center:  
Mail Stn:  BCM120
A5.  Funding Source:
     Baylor College of Medicine (Internal Funding Only)
A6a.  Institution(s) where work will be performed:
     TCH: Texas Children's Hospital
A6b.  Research conducted outside of the United States:
     
Country:  
 
Facility/Institution:  
 
Contact/Investigator:  
 
Phone Number:  
 
 
If documentation of assurances has not been sent to the Office of Research, please explain:
 
A7.  Research Category:
     
A8. Therapeutic Intent
Does this trial have therapeutic intent?
     Not set yet
 
A9. ClinicalTrails.gov Registration
 
Section B:  Review Path Determination
B1.  Full Board or Expedited Review
Is this an compassionate/emergency use situation?
     No
If this is a drug study, is an investigational new drug (IND) application required?
     Yes
If this is a device study, is an investigational device exemption (IDE) application required?
     N/A
If the research involves ONLY blood collection, are subjects healthy, non-pregnant adults whose weight is at least 110
pounds, with amount drawn less than 550 ml in an 8 week period, and with collection not occurring more frequently than 2
times per week?
     N/A
If the research involves ONLY blood collection for other adults and children, considering age, weight and health of subjects, is
the amount drawn in an 8 week period less than 50ml or 3 ml per kg, and with collection not occurring more frequently than 2
times per week?
     N/A
Does the research involve ONLY the collection of biological specimens for research purposes by noninvasive means? (e.g.
Hair; extracted teeth; excreta, sputum and external secretions; placenta removed at delivery; mucosal and skin cells collected
by scraping or swab)
     N/A
Does the research involve ONLY the collection of data through noninvasive procedures (not involving general anesthesia or
sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves? (e.g. EKG, ECHO,
EEG, Ultrasound, MRI)
     N/A
Does the research involve ONLY materials (data, documents, records, or specimens) that have been collected, or will be
collected solely for non-research purposes (such as medical treatment or diagnosis)?
     N/A

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Does the research involve ONLY the collection of data from voice, video, digital, or image recordings made for research
purposes?
     N/A
Does the research involve ONLY individual or group characteristics or behavior (including, but not limited to, research on
perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or
research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality
assurance methodologies?
     N/A
Does the research involve pedigree studies, collection and/or storage of specimens for DNA analysis or gene transfer?
     No
B2.  Exempt From IRB Review
     Not Applicable
 
B3.  Waiver of Subject Authorization
     Not Applicable
Section C:  Background Information
     
Dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, has recently been approved for use by the FDA for
sedation in adult critically ill patients. Perioperative use of this drug has been associated with reduced anesthetic
requirements, sedation without respiratory depression and, in adults, a decrease in postoperative requirement of
analgesics. In a recent study we conducted (H-16272), dexmedetomidine at a dose of 0.5 mcg/kg appeared to be
equivalent to morphine at a dose of 0.05mcg/kg with regards to adequacy of pain control and sedation following
tonsillectomy and/or adenoidectomy surgery. Tonsillectomy and adenoidectomy (T&A) is a common operation performed in
children, some of whom have obstructive sleep apnea or frequent tonsillitis. It is usually associated with a moderate
degree of post operative pain requiring narcotics. However, the use of narcotics may further aggravate postoperative
somnolence in some of these patients. Dexmedetomidine may decrease the need for post-operative narcotics thereby
reducing the incidence of somnolence following surgery.
 
Section D:  Purpose and Objectives
     
The primary purpose of this study is to determine the dose related efficacy of dexmedetomidine in the management of
postoperative pain in the pediatric patient undergoing tonsillectomy with or without adenoidectomy. The secondary
purpose is to determine the dose of dexmedetomidine that will be superior to morphine, in providing analgesia and also
decreasing somnolence following tonsillectomy with or without adenoidectomy.
 
Section E:  Protocol Risks/Subjects
E1.  Risk Category
     Category 2: Research involving greater than minimal risk, but presenting the prospect of direct benefit to the individual
subjects.
E2.  Subjects
Gender:
     Both
Age:
     Adolescent (13-17 yrs), Child (3-12 yrs)
Ethnicity:
     All Ethnicities
Primary Language:
     English, Spanish
Groups to be recruited will include:
     Patients
Which if any of the following vulnerable populations will be recruited as subjects?

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     Children
Vulnerable populations require special protections.  How will you obtain informed consent, protect subject confidentiality, and
prevent undue coercion?
     
Subjects and/or parents/guardians will be approached during routine pre-operative anesthesia workup. At this time, the
study will be explained with emphasis on the voluntary nature of participation. In children 7 years and above, assent will be
obtained. A Spanish translator and short Spanish consent will be available for Spanish speakers. Subjects and
parents/guardians will be assured that confidentiality of records will be maintained and that subject identifiers will be
removed prior to publication of findings. Refusal to participate in the study will not preclude subjects from receiving
standard anesthetic care.
E3.  Pregnant woman/fetus
Will pregnant women and/or fetuses (as described in 45 CFR 46 Subpart B) be enrolled in the research?
     No
E4.  Neonates
Will neonates of uncertain viability or nonviable neonates (as described in 45 CFR 46 Subpart B) be enrolled in the research?
     No
E5.  Children
Will children be enrolled in the research?
     Yes
 
Section F:  Design/Procedure
F1.  Design
Select one category that most adequately describes your research:
     z.z) ARCHIVED DO NOT USE - Other
Discuss the research design including but not limited to such issues as: probability of group assignment, potential for subject
to be randomized to placebo group, use of control subjects, etc.
     This will be a prospective randomized controlled study.
Inclusion Criteria:
     Children who are classified as American Society of Anesthesiology (ASA) Class 1 and 2, between 3 to 17 years of age
undergoing Tonsillectomy with or without Adenoidectomy will be included in the study.
Exclusion Criteria:
     
This will exclude children less than three years of age, females with a positive pregnancy test, those with uncorrected
cardiac lesions as determined by a history of cyanotic congenital heart lesions pending surgical correction, as well as
children classified as ASA 3 or 4. Children with diagnosed heart block or liver impairment will also be excluded from the
study.
F2.  Procedure
     Subjects will receive oral midazolam 0.5 mg/kg as premedication (10 mg maximum dose). They will be randomized
preoperatively to receive either morphine 0.05 mg/kg, morphine 0.1 mg/kg or dexmedetomidine at one of the following
doses: 0.75mcg/kg or 1mcg/kg. Routine intraoperative monitors will be applied, which at Texas Children's Hospital include
pulse oximeter, heart rate monitors and non-invasive oscillometric blood pressure. These are all routine monitors and not
part of the study protocol. General anesthesia will be induced with nitrous oxide, oxygen and sevoflurane via mask. After
establishment of intravenous access, tracheal intubation will be facilitated with atracurium 0.5mg/kg IV. Once the
endotracheal tube has been secured, the patient will receive morphine 0.05 mg/kg, morphine 0.1 mg/kg or
dexmedetomidine at a dose of 0.75mcg/kg or 1mcg/kg (based on prior randomization) over 10 minutes. The practitioner
will be blinded as to which medication the patient is receiving. Postoperatively, the patients will be transferred to the post
anesthetic care unit where a blinded observer will record heart rate, respiratory rate and arterial blood pressure every 5
minutes for the first 15 minutes and every 15 minutes for 60 minutes. The patients' excitement will also be graded on a
scale of 0-4 (0=no excitement and 4= severe excitement) for the same duration with documentation every 15 minutes.
Supplemental Oxygen will be administered to keep the oxygen saturation above 95%. Pain will be assessed using the
Children's Hospital of Eastern Ontario Pain scale (CHEOPS). Additional Morphine, in incremental doses of 25ug/kg, will be
administered for CHEOPS score greater than 8. The time to first oral intake will also be recorded. The primary endpoint
will be the amount of narcotics required to make the patient comfortable in the post anesthesia recovery unit. The
secondary end point will be the patient's level of somnolence. Using the Ramsay scale, somnolence will be assessed at 15
minute intervals. The Ramsay score assigns a score of 1-6 based on the clinical assessment of the level of sedation (1 =
anxious, agitated, restless; 2 = awake but co-operative, tranquil, orientated; 3 = responds to verbal command only; scores

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4-6 are an asleep patient and are graded according to the response to a loud noise or glabellar tap: 4 = brisk response, 5
= sluggish response; 6 = no response).
 
Section G:  Sample Size/Data Analysis
G1.  Sample Size
How many subjects (or specimens, or charts) will be used in this study?
     Local: 240              Worldwide: 240
Please indicate why you chose the sample size proposed:
     
This power analysis is for a one-way fixed effects analysis of variance with 4 levels. The groups are formed based on the
drug and dosage levels: 1) morphine 0.05 mg/kg 2) morphine 0.1 mg/kg 3) dexmedetomidine 0.75mcg/kg, or 3)
dexmedetomidine 1mcg/kg. The study will include 60 cases per group for a total of 240 cases. The criterion for
significance (alpha) has been set at 0.05. The analysis of variance is non-directional (i.e. two-tailed) which means that an
effect in either direction will be interpreted. The effect size (f) is expected to be moderate 0.25, which yields power of 0.80.
An interim analysis is planned after 100 cases have been randomized to reassess the sample requirements for this study.
G2.  Data Analysis
Provide a description of your plan for data analysis. State the types of comparisons you plan (e.g. comparison of means,
comparison of proportions, regressions, analysis of variance). Which is the PRIMARY comparison/analysis? How will the
analyses proposed relate to the primary purposes of your study?
     
Data analysis for the primary outcome variable in this protocol will be an analysis of variance. The primary outcome
variable will be the total amount of additional morphine required following surgery. The main effect of drug/dose will
determine if there are differences in the amount of additional morphine needed following surgery in the four groups. If the
main effect shows a significant difference then post hoc contrasts will compare the morphine 0.05 mg/kg group and the
morphine 0.1 mg/kg group to each of the dexmedetomidine dosage groups to determine if there is a significant difference
between the groups. The secondary outcome variable is the level of somnolence as measured by the Ramsay scale. This
is a rating that provides ordinal data, which will be analyzed using appropriate non-parametric approaches assuming equal
dispersion of ratings in each drug\dose group.
 
Section H:  Potential Risks/Discomforts
Describe and assess any potential risks/discomforts; (physical, psychological, social, legal, or other) and assess the likelihood
and seriousness of such risks:
     Dexmedetomidine has been investigated in the adult population for sedative and analgesic properties. It has also been
studied in the pediatric population for procedural sedation, sedation during mechanical ventilation and for weaning patients
on mechanical ventilation with chronic narcotic dependence. The potential unfavorable changes with use of this drug in the
literature include hypotension and bradycardia, mostly seen with infusion of the drug at high doses and also observed
when administered to patients concomitantly taking drugs with negative chronotropic effects. Changes in blood pressure
and heart rate seen usually did not exceed 30% of baseline; these anticipated blood pressure and heart rate changes are
not different than those observed with morphine. Alterations in cardiovascular variables will be avoided by administering
lower doses of the drug as well as careful patient selection. The criteria for stopping the study in an individual patient (i.e.
during study drug administration) will include: immediate skin reaction at site of administration, heart block, anaphylaxis,
severe bradycardia resulting in a 30 mmHg or greater drop in systolic blood pressure, or sudden hypotension. The number
of patients with adverse events or serious adverse events that would result in stopping the trial in general are as follows:
a). Asystole: If 1 patient develops asystole, appropriate resuscitation measures will be instituted and the cause will be
investigated, If the etiology of asystole is found not to be related solely to the drug, the study would continue. If however,
no other cause can be determined and the event is deemed to occur primarily as a result of the drug then the study would
be stopped.
 
 
b). Heart block: This is known to occur if dexmedetomidine is used in patients that are currently taking negative
chronotropic agents. The use of negative chronotropic agents is an exclusion criterion for participation in this study. If heart
block occurs despite the precautions, it would be treated and investigated thoroughly. If it were found to occur solely as a
result of dexmedetomidine, the study would be stopped after observing this in 2 patients.
 
 
c). Persistent hypotension: This is defined by hypotension that does not respond to crsytalloids or vasoactive medication. If
this occurs in 3 patients, and is evaluated to occur solely as a result of dexmedetomidine, the study would be stopped.
 
 
d). Severe persistent bradycardia: This will be defined as bradycardia less than 60 beats per minute that results in an
accompanying decrease in systolic blood pressure (greater than 30 mmHg decrease). If this occurs in 3 patients and no
other cause is found, the study would be stopped. 
 
 
e). Anaphylaxis: This will be investigated and if no other reason is found, the study will be stopped if it is observed in 2
patients.
 
 

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f). Skin reaction at the site of administration: This would be further classified into mild skin reaction or severe and
generalized skin reaction. i. If severe and generalized skin reaction occurs in 3 patients and is believed to occur as a result
of dexmedetomidine, the study would be stopped. ii. If a localized skin reaction occurs in 3 patients and is believed to
occur as a result of dexmedetomidine the study would be stopped.
 
 
 
Section I:  Potential Benefits
Describe potential benefit(s) to be gained by the individual subject as a result of participating in the planned work.
     
Postoperative pain and oxygen requirement following Tonsillectomy and Adenoidectomy continues to be a major etiology
of prolonged post anesthesia recovery room stay. The analgesia sparing effects of dexmedetomidine as well as the effects
of sedation without respiratory depression may allow for quicker postoperative recovery from this surgery.
Describe potential benefit(s) to society of the planned work.
     It is possible that dexmedetomidine will decrease the need for perioperative analgesia following this surgery thereby
allowing quicker transition through the recovery room phase and reducing hospital as well as patient cost.
Do anticipated benefits outweigh potential risks? Discuss the risk-to-benefit ratio.
     
The risk to benefit ratio is low, routine anesthetic monitoring during and after surgery will not be altered by this study.
Expected heart rate and blood pressure changes seen with dexmedetomidine are not different from those seen with
morphine, a drug routinely used in general anesthesia. The very small risk to a subject from study participation would not
outweigh the potential benefit to society that may result from study findings.
 
Section J:  Consent Procedures
J1.  Waiver of Consent
Will this research require a waiver of consent and authorization?
     No
Will additional pertinent information be provided to subjects after participation?
     No
Explain why providing subjects additional pertinent information after participation is not appropriate.
     
J1a.  Waiver of requirement for written documentation of Consent
Is this research subject to FDA regulations?
     No
Explain how the research involves no more than minimal risk to the participants, and the specifics demonstrating that the
research does not involve procedures for which written consent is normally required outside of the research context.
     
Explain how the only record linking the participant and the research would be the consent document, and how the principal
risk would be potential harm resulting from a breach of confidentiality, and how each participant will be asked whether he or
she wants documentation linking the participant with the research and their wishes will govern.
     
J2.  Consent Procedures
Who will recruit subjects for this study?
     PI
 
PI's staff
Describe how research population will be identified, recruitment procedures, any waiting period between informing the
prospective participant and obtaining consent, steps taken to minimize the possibility of coercion or undue influence and
consent procedures in detail.
     
Subjects will be identified from the pediatric surgery schedule for Texas Children's Hospital, which is routinely available to
the Division of General Pediatric Anesthesia for the purpose of pre-operative evaluation. The PI, co-investigators, or staff
will approach subjects meeting the inclusion criteria, and the study will be explained with emphasis on the voluntary nature
of participation. A Spanish translator and short Spanish version of the consent will be available for Spanish speakers.
Consent may be obtained from one or both parents (Texas law allows consent to be obtained from one parent) and the
child clause will be included in the consent i.e. the parent can state that the child assents according to his or her own level
of understanding.
Are foreign language consent forms required for this protocol?

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     Yes
Which of the following ways will you document informed consent in languages other than English?
     Short-Form consent documents
J3.  Privacy and Intrusiveness
Will the research involve observation or intrusion in situations where the subjects would normally have an expectation of
privacy?
     No
J4.  Children
Will children be enrolled in the research?
     Yes
J5.  Neonates
Will non-viable neonates or neonates of uncertain viability be involved in research?
     No
J6.  Consent Capacity - Adults who lack capacity
Will Adult subjects who lack the capacity to give informed consent be enrolled in the research?
     No
J7.  Prisoners
Will Prisoners be enrolled in the research?
     No
 
Section K:  Confidentiality
Will research data include health information by which subjects can be identified?
     Yes
Where will research data be kept? How will such data be secured?
     Data will be kept in a locked file cabinet in the PI's office. Computer data sets will be password protected.
Who, besides the PI, the study staff, the IRB and the sponsor, will have access to identifiable research data?
     Data will be available only to the PI, co-investigators , and staff.
 
Will you obtain a Certificate of Confidentiality for this study?
     No
Please further discuss any potential confidentiality issues related to this study.
     NA
 
Section L:  Cost/Payment
Delineate clinical procedures from research procedures. Will subject's insurance (or subject) be responsible for research
related costs? If so state for which items subject's insurance (or subject) will be responsible (surgery, device, drugs, etc). If
appropriate, discuss the availability of financial counseling.
     The research procedures consist of the drug administration protocol. There will be no charge to the subject or subject's
insurance company.
If subjects will be paid (money, gift certificates, coupons, etc.) to participate in this research project, please note the total
dollar amount (or dollar value amount) and distribution plan (one payment, pro-rated payment, paid upon completion, etc) of
the payment.
Dollar Amount:
     0
Distribution Plan:
     
 

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Section M:  Genetics
How would you classify your genetic study?
     
Discuss the potential for psychological, social, and/or physical harm subsequent to participation in this research. Please
discuss, considering the following areas: risks to privacy, confidentiality, insurability, employability, immigration status,
paternity status, educational opportunities, or social stigma.
     
Will subjects be offered any type of genetic education or counseling, and if so, who will provide the education or counseling
and under what conditions will it be provided? If there is the possibility that a family's pedigree will be presented or published,
please describe how you will protect family member's confidentiality?
     
 
Section N:  Sample Collection
None
 
Section O:  Drug Studies
Is this study placebo-controlled?
     No
Does the research involve a drug or biologic (including radioactive drugs) that is not approved by the FDA?
     No
Will the research involve a radioactive drug?
     No
IND Number:
     79,290
 
Section P:  Device Studies
Does this study need an IDE?
     No
Regarding your device study, could potential harm to subjects be life-threatening?
     No
Regarding your device study, could potential harm to subjects result in permanent impairment of a body function?
     No
Regarding your device study, could potential harm to subjects result in permanent damage to a body structure?
     No
 
Section Q.  Consent Form(s)
Consent form elliciting possible participation in a double-blind, randomized study examining dexmedetomidine and morphine
for analgesia in children having adenotonsillectomy
 
Section R:  Advertisements
None