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出境医 / 临床实验 / Intranasal Dexmedetomidine Dose-finding Study

Intranasal Dexmedetomidine Dose-finding Study

Study Description
Brief Summary:
The most common injury prompting an emergency department (ED) visit in children is a cut (laceration) that requires repair using stitches or skin glue. Despite anesthetic (freezing), laceration repair is often very distressful because in young children, most occur on the face. There is currently no effective drug to relieve the distress of laceration repair in children. The goal is to find a safe and effective drug to reduce distress in children undergoing laceration repair. Dexmedetomidine is a new drug that safely provides mild sedation and can be given as a painless nasal spray. Intranasal dexmedetomidine (IND) has been shown to reduce distress in children undergoing painful procedures such as dental work and intravenous insertion. However, no large study has explored IND for laceration repair. In order for research to change the way we care for children, a large study that enrolls children across many paediatric EDs needs to be performed. The first step is to conduct a smaller study to identify the safest and most effective dose. The proposed study plans to enroll 55 children age 1-10 years who require laceration repair.

Condition or disease Intervention/treatment Phase
Laceration Repair Drug: Dexmedetomidine Phase 2

Detailed Description:

Design: This study will be designed as a phase II single-arm dose-escalation pilot study using the continual reassessment method.

Protocol: Sedation will be measured using the Pediatric Sedation State Scale (PSSS), an instrument validated for video scoring of children undergoing painful procedures. The PSSS is scored from 0 (dangerously sedated) to 5 (least sedated) easily by non-medical personnel and assesses over sedation and under sedation. Adequate sedation is a score of 2 or 3. Participants will be consecutively assigned to increasing doses of IND from 1-4 mcg/kg based on the continual reassessment method. Participants will be assigned to doses of IND from 1-4 mcg/kg, increasing in whole number increments. Initially three participants will receive 1mcg/kg and the number of participants at each dose of IND will be recorded. Data from these participants will be used to update a Bayesian model for the dose-response curve for all three categories of sedation. The following three participants will be assigned the dose with the highest posterior probability of an efficacy close to 0.8. This balances the need to determine the most efficacious dose but prevents an excessive number of over-sedations. For the Bayesian dose response model, a determination will be made as to the overall score category for each participant ("adequate", "over", or "under sedated" based on the PSSS). To be scored as "adequate", a participant must have a PSSS score of 2 or 3 for at least 90% of observations from initial positioning to tying of the last suture. If a participant does not retain a PSSS score of 2 or 3 for at least 90% of the observations, they will be categorized as either over or under-sedated, if the majority of the remaining PSSS scores are 0 or 1 or 4 or 5, respectively. Furthermore, if the participant remains awake, but not distressed during the procedure, they will be scored as a 2 based on the PSSS. However, for the purposes of the Bayesian dose response model, they will be scored as "under sedated" to avoid concluding that a lower dose of IND is effective based on the outcomes for participants that did not require sedation. Finally, participants who are noncompliant with IND will be categorized as an over-sedation as it is assumed that this dose was not well tolerated by the participant and dose escalation should be avoided. Data will be reviewed after each dose increment by a data safety monitoring board, who will confirm it is safe to escalate. Permissible co-interventions include topical and subcutaneous anesthetic, oral or IV analgesics, non-pharmacologic strategies for pain and distress.

Screening and Enrollment: Participants will be consecutively screened for eligibility during the hours of study recruitment.

Sample Size: This was calculated using the Bayesian continual reassessment method (20). Based on an adverse event rate of 10%, 4 dosing levels, an odds ratio for the effect size of 1.8, and a phase II trial accuracy level of 60%, an estimated a sample size of 55 participants was calculated.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 55 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Dose-escalation pilot study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Blinding of dose levels will not be possible so outcome assessors will be blinded by virtue of being remote from the clinical encounter. Furthermore, video segments will commence immediately after intranasal sprays are given so outcome assessors will not see what volume is administered. Two independent assessors will score each video and an interrater agreement (kappa) will be calculated.
Primary Purpose: Treatment
Official Title: Intranasal Dexmedetomidine for Laceration Repair in Children: a Dose-finding Study
Actual Study Start Date : February 20, 2020
Estimated Primary Completion Date : September 1, 2021
Estimated Study Completion Date : September 1, 2021
Arms and Interventions
Arm Intervention/treatment
Experimental: Dexmedetomidine 1 mcg/kg
Intranasal dexmedetomidine 100 mcg/mL (Precedex, Pfizer) 1 mcg/kg (max 100 mcg or 1 mL).
Drug: Dexmedetomidine
Intranasal dexmedetomidine

Active Comparator: Dexmedetomidine 2 mcg/kg
Intranasal dexmedetomidine 100 mcg/mL (Precedex, Pfizer) 2 mcg/kg (max 100 mcg or 1 mL).
Drug: Dexmedetomidine
Intranasal dexmedetomidine

Active Comparator: Dexmedetomidine 3 mcg/kg
Intranasal dexmedetomidine 100 mcg/mL (Precedex, Pfizer) 3 mcg/kg (max 100 mcg or 1 mL).
Drug: Dexmedetomidine
Intranasal dexmedetomidine

Active Comparator: Dexmedetomidine 4 mcg/kg
Intranasal dexmedetomidine 100 mcg/mL (Precedex, Pfizer) 4 mcg/kg (max 100 mcg or 1 mL).
Drug: Dexmedetomidine
Intranasal dexmedetomidine

Outcome Measures
Primary Outcome Measures :
  1. Adequate sedation [ Time Frame: Index visit ]
    The number of participants with adequate sedation defined as a PSSS or 2 or 3 for the duration of the measurement period (initial positioning to tying of the last suture)


Secondary Outcome Measures :
  1. Onset of sedation [ Time Frame: Index visit ]
    Time to adequate sedation (based on PSSS score)

  2. Adverse effects [ Time Frame: Index visit ]
    The number of participants with adverse effects based on the Quebec Guidelines for Reporting of Adverse Effects in Children

  3. Anxiolysis [ Time Frame: Index visit ]
    Degree of anxiolysis as measured using the modified Yale Preoperative Anxiety Scale (mYPAS). The mYPAS is an observationale scale consisting of 22 items across 5 categories. The total score ranges from 0 to 100 with higher scores indicating greater anxiety.

  4. Compliance [ Time Frame: Index visit ]
    Number of participants deemed a compliant with intervention administration

  5. Satisfaction with laceration repair: 5-item Likert scale [ Time Frame: Index visit ]
    Satisfaction score using a 5-item Likert scale obtained from the caregiver, child (if > 7 years), individual performing the repair, and bedside nurse

  6. Nasal irritation [ Time Frame: Index visit ]
    Score on the Faces Pain Scale - Revised (FPS-R) and obtained from children age > 4 years

  7. Length of stay [ Time Frame: Index visit ]
    Duration of time from triage assessment to discharge time

  8. Consent rate [ Time Frame: Index visit ]
    Proportion of eligible participants consented

  9. Delayed maladaptive behaviors [ Time Frame: 48 hours post-discharge ]
    Proportion of children with delayed maladaptive behaviors measured with the Post-Hospital Behavior Questionnaire (PHBQ) assessed 24-48 hours post discharge. The PHBQ is comprised of 27 items among six subscales (general anxiety and regression, separation anxiety, eating disturbance, aggression toward authority, apathy/withdrawal, anxiety about sleep. For each item, parents are asked to compare their child's behavior before hospitalization to their current behavior (post-hospitalization) on a Likert-type scale using the following five response options: much less than before (1), less than before (2), same as before (3), more than before (4), and much more than before (5), producing a range from 27-135 with higher scores indicating greater severity of maladaptive behaviors.

  10. Wound complications [ Time Frame: 14 days post-discharge ]
    Number of participants with wound complications within 14 days of discharge (infection; dehiscence; contracture; retained suture material).


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   1 Year to 10 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • children age 1-10 years who present to the ED with an isolated laceration < 5 cm
  • deemed to require suture repair based on the opinion of the treating physician
  • predicted to resist positioning for laceration repair based on the opinion of the caregiver

Exclusion Criteria:

  • laceration repair requiring procedural sedation (without IND) or local nerve block, - other injuries requiring reduction (fracture or dislocation) or repair (nailbed injury or laceration)
  • lacerations containing foreign body material (including dirt and debris)
  • history of hypersensitivity to dexmedetomidine
  • occlusion of at least one nare due to mucus, polyps, septal deviation, etc.
  • concomitant use of an alpha 2-adrenergic receptor agonist
  • bradycardia or hypotension for age (possible transient but clinically insignificant adverse effects of dexmedetomidine)
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Naveen Poonai 5196858500 naveen.poonai@lhsc.on.ca

Locations
Layout table for location information
Canada, Ontario
London Health Sciences Centre Recruiting
London, Ontario, Canada, N6A5W9
Contact: Naveene Poonai, MD    5196945309    naveen.poonai@lhsc.on.ca   
Sponsors and Collaborators
Lawson Health Research Institute
Tracking Information
First Submitted Date  ICMJE May 17, 2019
First Posted Date  ICMJE May 21, 2019
Last Update Posted Date May 7, 2021
Actual Study Start Date  ICMJE February 20, 2020
Estimated Primary Completion Date September 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 4, 2021)
Adequate sedation [ Time Frame: Index visit ]
The number of participants with adequate sedation defined as a PSSS or 2 or 3 for the duration of the measurement period (initial positioning to tying of the last suture)
Original Primary Outcome Measures  ICMJE
 (submitted: May 20, 2019)
Adequate sedation [ Time Frame: Index visit ]
Defined as a Dartmouth Operative Conditions Scale (DOCS) from -2 to +2) for the duration of the measurement period ((every 30 seconds from the start of preprocedural positioning to tying of the last suture)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 4, 2021)
  • Onset of sedation [ Time Frame: Index visit ]
    Time to adequate sedation (based on PSSS score)
  • Adverse effects [ Time Frame: Index visit ]
    The number of participants with adverse effects based on the Quebec Guidelines for Reporting of Adverse Effects in Children
  • Anxiolysis [ Time Frame: Index visit ]
    Degree of anxiolysis as measured using the modified Yale Preoperative Anxiety Scale (mYPAS). The mYPAS is an observationale scale consisting of 22 items across 5 categories. The total score ranges from 0 to 100 with higher scores indicating greater anxiety.
  • Compliance [ Time Frame: Index visit ]
    Number of participants deemed a compliant with intervention administration
  • Satisfaction with laceration repair: 5-item Likert scale [ Time Frame: Index visit ]
    Satisfaction score using a 5-item Likert scale obtained from the caregiver, child (if > 7 years), individual performing the repair, and bedside nurse
  • Nasal irritation [ Time Frame: Index visit ]
    Score on the Faces Pain Scale - Revised (FPS-R) and obtained from children age > 4 years
  • Length of stay [ Time Frame: Index visit ]
    Duration of time from triage assessment to discharge time
  • Consent rate [ Time Frame: Index visit ]
    Proportion of eligible participants consented
  • Delayed maladaptive behaviors [ Time Frame: 48 hours post-discharge ]
    Proportion of children with delayed maladaptive behaviors measured with the Post-Hospital Behavior Questionnaire (PHBQ) assessed 24-48 hours post discharge. The PHBQ is comprised of 27 items among six subscales (general anxiety and regression, separation anxiety, eating disturbance, aggression toward authority, apathy/withdrawal, anxiety about sleep. For each item, parents are asked to compare their child's behavior before hospitalization to their current behavior (post-hospitalization) on a Likert-type scale using the following five response options: much less than before (1), less than before (2), same as before (3), more than before (4), and much more than before (5), producing a range from 27-135 with higher scores indicating greater severity of maladaptive behaviors.
  • Wound complications [ Time Frame: 14 days post-discharge ]
    Number of participants with wound complications within 14 days of discharge (infection; dehiscence; contracture; retained suture material).
Original Secondary Outcome Measures  ICMJE
 (submitted: May 20, 2019)
  • Onset and duration of sedation [ Time Frame: Index visit ]
    Based on DOCS score
  • Adverse effects [ Time Frame: Index visit ]
    Based on Health Canada checklist
  • Anxiolysis [ Time Frame: Index visit ]
    Measured using the Yale Preoperative Anxiety Scale (YPAS)
  • Compliance [ Time Frame: Index visit ]
    Compliance (yes/no) with intervention administration
  • Satisfaction with laceration repair: 5-item Likert scale [ Time Frame: Index visit ]
    Measuring using a 5-item Likert scale obtained from the caregiver, child (if > 7 years), individual performing the repair, and bedside nurse
  • Nasal irritation [ Time Frame: Index visit ]
    Obtained from children age > 4 years using the Faces Pain Scale - Revised (FPS-R)
  • Length of stay [ Time Frame: Index visit ]
    Based on registration to discharge time
  • Consent rate [ Time Frame: Index visit ]
    Proportion consented over eligible
  • Delayed maladaptive behaviors [ Time Frame: 48 hours post-discharge ]
    Measured with the Post-Hospital Behavior Questionnaire (PHBQ) assessed 24-48 hours post discharge
  • Wound complications [ Time Frame: 14 days post-discharge ]
    Within 14 days of discharge (infection; dehiscence; contracture; retained suture material).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Intranasal Dexmedetomidine Dose-finding Study
Official Title  ICMJE Intranasal Dexmedetomidine for Laceration Repair in Children: a Dose-finding Study
Brief Summary The most common injury prompting an emergency department (ED) visit in children is a cut (laceration) that requires repair using stitches or skin glue. Despite anesthetic (freezing), laceration repair is often very distressful because in young children, most occur on the face. There is currently no effective drug to relieve the distress of laceration repair in children. The goal is to find a safe and effective drug to reduce distress in children undergoing laceration repair. Dexmedetomidine is a new drug that safely provides mild sedation and can be given as a painless nasal spray. Intranasal dexmedetomidine (IND) has been shown to reduce distress in children undergoing painful procedures such as dental work and intravenous insertion. However, no large study has explored IND for laceration repair. In order for research to change the way we care for children, a large study that enrolls children across many paediatric EDs needs to be performed. The first step is to conduct a smaller study to identify the safest and most effective dose. The proposed study plans to enroll 55 children age 1-10 years who require laceration repair.
Detailed Description

Design: This study will be designed as a phase II single-arm dose-escalation pilot study using the continual reassessment method.

Protocol: Sedation will be measured using the Pediatric Sedation State Scale (PSSS), an instrument validated for video scoring of children undergoing painful procedures. The PSSS is scored from 0 (dangerously sedated) to 5 (least sedated) easily by non-medical personnel and assesses over sedation and under sedation. Adequate sedation is a score of 2 or 3. Participants will be consecutively assigned to increasing doses of IND from 1-4 mcg/kg based on the continual reassessment method. Participants will be assigned to doses of IND from 1-4 mcg/kg, increasing in whole number increments. Initially three participants will receive 1mcg/kg and the number of participants at each dose of IND will be recorded. Data from these participants will be used to update a Bayesian model for the dose-response curve for all three categories of sedation. The following three participants will be assigned the dose with the highest posterior probability of an efficacy close to 0.8. This balances the need to determine the most efficacious dose but prevents an excessive number of over-sedations. For the Bayesian dose response model, a determination will be made as to the overall score category for each participant ("adequate", "over", or "under sedated" based on the PSSS). To be scored as "adequate", a participant must have a PSSS score of 2 or 3 for at least 90% of observations from initial positioning to tying of the last suture. If a participant does not retain a PSSS score of 2 or 3 for at least 90% of the observations, they will be categorized as either over or under-sedated, if the majority of the remaining PSSS scores are 0 or 1 or 4 or 5, respectively. Furthermore, if the participant remains awake, but not distressed during the procedure, they will be scored as a 2 based on the PSSS. However, for the purposes of the Bayesian dose response model, they will be scored as "under sedated" to avoid concluding that a lower dose of IND is effective based on the outcomes for participants that did not require sedation. Finally, participants who are noncompliant with IND will be categorized as an over-sedation as it is assumed that this dose was not well tolerated by the participant and dose escalation should be avoided. Data will be reviewed after each dose increment by a data safety monitoring board, who will confirm it is safe to escalate. Permissible co-interventions include topical and subcutaneous anesthetic, oral or IV analgesics, non-pharmacologic strategies for pain and distress.

Screening and Enrollment: Participants will be consecutively screened for eligibility during the hours of study recruitment.

Sample Size: This was calculated using the Bayesian continual reassessment method (20). Based on an adverse event rate of 10%, 4 dosing levels, an odds ratio for the effect size of 1.8, and a phase II trial accuracy level of 60%, an estimated a sample size of 55 participants was calculated.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
Dose-escalation pilot study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Blinding of dose levels will not be possible so outcome assessors will be blinded by virtue of being remote from the clinical encounter. Furthermore, video segments will commence immediately after intranasal sprays are given so outcome assessors will not see what volume is administered. Two independent assessors will score each video and an interrater agreement (kappa) will be calculated.
Primary Purpose: Treatment
Condition  ICMJE Laceration Repair
Intervention  ICMJE Drug: Dexmedetomidine
Intranasal dexmedetomidine
Study Arms  ICMJE
  • Experimental: Dexmedetomidine 1 mcg/kg
    Intranasal dexmedetomidine 100 mcg/mL (Precedex, Pfizer) 1 mcg/kg (max 100 mcg or 1 mL).
    Intervention: Drug: Dexmedetomidine
  • Active Comparator: Dexmedetomidine 2 mcg/kg
    Intranasal dexmedetomidine 100 mcg/mL (Precedex, Pfizer) 2 mcg/kg (max 100 mcg or 1 mL).
    Intervention: Drug: Dexmedetomidine
  • Active Comparator: Dexmedetomidine 3 mcg/kg
    Intranasal dexmedetomidine 100 mcg/mL (Precedex, Pfizer) 3 mcg/kg (max 100 mcg or 1 mL).
    Intervention: Drug: Dexmedetomidine
  • Active Comparator: Dexmedetomidine 4 mcg/kg
    Intranasal dexmedetomidine 100 mcg/mL (Precedex, Pfizer) 4 mcg/kg (max 100 mcg or 1 mL).
    Intervention: Drug: Dexmedetomidine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 4, 2021)
55
Original Estimated Enrollment  ICMJE
 (submitted: May 20, 2019)
54
Estimated Study Completion Date  ICMJE September 1, 2021
Estimated Primary Completion Date September 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • children age 1-10 years who present to the ED with an isolated laceration < 5 cm
  • deemed to require suture repair based on the opinion of the treating physician
  • predicted to resist positioning for laceration repair based on the opinion of the caregiver

Exclusion Criteria:

  • laceration repair requiring procedural sedation (without IND) or local nerve block, - other injuries requiring reduction (fracture or dislocation) or repair (nailbed injury or laceration)
  • lacerations containing foreign body material (including dirt and debris)
  • history of hypersensitivity to dexmedetomidine
  • occlusion of at least one nare due to mucus, polyps, septal deviation, etc.
  • concomitant use of an alpha 2-adrenergic receptor agonist
  • bradycardia or hypotension for age (possible transient but clinically insignificant adverse effects of dexmedetomidine)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 10 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Naveen Poonai 5196858500 naveen.poonai@lhsc.on.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03957304
Other Study ID Numbers  ICMJE 51384
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Lawson Health Research Institute
Study Sponsor  ICMJE Lawson Health Research Institute
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Lawson Health Research Institute
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP