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| Name | Class |
|---|---|
| Emergency Medicine Foundation | OTHER |
| Mailman School of Public Health | UNKNOWN |
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Dose-finding study to compare intranasal midazolam doses of 0.2, 0.3, 0.4 and 0.5 mg/kg in children undergoing laceration repair to achieve the following aims:
Specific Aim #1: To determine the most effective dose of intranasal midazolam for producing adequate sedation state associated with each dose.
Specific Aim #2: To determine the time to recovery and describe the adverse events associated with each dose.
Intranasal midazolam is a common and effective sedative whose use in children presenting to emergency departments has been described. However, the doses of intranasal midazolam used have varied greatly, with no identified optimal dose. Doses most commonly described in literature reviews, research studies, and clinical guidelines range from 0.2 to 0.5 mg/kg. There is only one study, retrospective, that compares doses and suggests that clinical efficacy is improved with higher doses, without any clear difference in safety. There is a need for a rigorously-conducted trial to determine the dose of intranasal midazolam that optimizes the adequacy of sedation state without leading to adverse events or compromising emergency department-centric outcomes such as time to onset of sedation and time to recovery. To fill this important and persistent gap in knowledge, the investigator will conduct a dose-finding study using an adaptive trial design to compare intranasal midazolam doses of 0.2, 0.3, 0.4, and 0.5 mg/kg in children undergoing laceration repairs, one of the most common types of minor trauma treated in emergency departments.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 0.2 mg/kg | Experimental | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.2 mg/kg. |
|
| 0.3 mg/kg | Experimental | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.3 mg/kg. |
|
| 0.4 mg/kg | Experimental | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.4 mg/kg. |
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| 0.5 mg/kg | Experimental | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.5 mg/kg. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Intranasal midazolam | Drug | 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Children Who Achieved PSSS Score 2, 3, or 4 for 95% or Greater of the Scored Procedure | The Pediatric Sedation State Scale (PSSS) is scored from 0 to 5, representing a continuum of sedation that spans from over-sedation associated with changes in vital signs (0) to inadequate sedation (5). | From study drug administration until procedure finished (approximately 60 minutes) |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Recovery | Time (in minutes) from procedure completion until a Simplified Aldrete Score (SAS) of at least 6 is achieved. The score ranges from 0 (lowest) to 8 (highest). If a patient already fulfills criteria for recovery at procedure start, then time to recovery is 0. | From study drug administration until patient discharge (approximately 120 minutes) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Daniel S. Tsze, MD, MPH | Columbia University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| NewYork Presbyterian Morgan Stanley Children's Hospital | New York | New York | 10032 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27823876 | Background | Tsze DS, Ieni M, Fenster DB, Babineau J, Kriger J, Levin B, Dayan PS. Optimal Volume of Administration of Intranasal Midazolam in Children: A Randomized Clinical Trial. Ann Emerg Med. 2017 May;69(5):600-609. doi: 10.1016/j.annemergmed.2016.08.450. Epub 2016 Nov 4. | |
| 28557732 | Background | Cravero JP, Askins N, Sriswasdi P, Tsze DS, Zurakowski D, Sinnott S. Validation of the Pediatric Sedation State Scale. Pediatrics. 2017 May;139(5):e20162897. doi: 10.1542/peds.2016-2897. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 0.2 mg/kg | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.2 mg/kg. Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. |
| FG001 | 0.3 mg/kg | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.3 mg/kg. Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. |
| FG002 | 0.4 mg/kg | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.4 mg/kg. Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. |
| FG003 | 0.5 mg/kg | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.5 mg/kg. Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 0.2 mg/kg | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.2 mg/kg. Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. |
| BG001 | 0.3 mg/kg |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Children Who Achieved PSSS Score 2, 3, or 4 for 95% or Greater of the Scored Procedure | The Pediatric Sedation State Scale (PSSS) is scored from 0 to 5, representing a continuum of sedation that spans from over-sedation associated with changes in vital signs (0) to inadequate sedation (5). | Posted | Count of Participants | Participants | From study drug administration until procedure finished (approximately 60 minutes) |
|
From time of intranasal midazolam administration until discharge from emergency department (approximately 120 minutes)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 0.2 mg/kg | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.2 mg/kg. Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Daniel Tsze MD MPH | Columbia University | 212-317-0997 | dst2141@cumc.columbia.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 6, 2021 | May 28, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D008874 | Midazolam |
| ID | Term |
|---|---|
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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Sequential selection procedure
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|
| Number of Adverse Events | Adverse events will be defined using the Pediatric Emergency Research Canada and Pediatric Emergency Care Applied Research Network Consensus-Based Recommendations. These adverse events include oxygen desaturation; apnea (central, obstructive, laryngospasm); clinically apparent pulmonary aspiration; retching/vomiting; bradycardia; hypotension; excitatory movements; paradoxical response to sedation; unpleasant recovery reactions; and permanent complications (including death). | From study drug administration until patient discharge (approximately 120 minutes) |
| Time to Onset of Minimal Sedation | Time (in minutes) from administration of intranasal midazolam until a University of Michigan Sedation State (UMSS) score of 1 is achieved. The UMSS represents a spectrum of depth of sedation ranging from unarousable (4) to awake and alert (0). Note: This outcome was initially listed as a primary outcome, but was changed to a secondary outcome in the IRB-approved protocol and prior to enrollment of the first patient. | From study drug administration until procedure finished (approximately 60 minutes) |
| UMSS Scale Score | Depth of sedation will be measured using the University of Michigan Sedation Scale (UMSS). This sedation scale ranges from zero to four with higher numbers indicating deeper sedation. | From study drug administration until procedure finished (approximately 60 minutes) |
| 28992870 | Background | Mellion SA, Bourne D, Brou L, Brent A, Adelgais K, Galinkin J, Wathen J. Evaluating Clinical Effectiveness and Pharmacokinetic Profile of Atomized Intranasal Midazolam in Children Undergoing Laceration Repair. J Emerg Med. 2017 Sep;53(3):397-404. doi: 10.1016/j.jemermed.2017.05.029. |
| Background | Leu C-S, Levin B. On the probability of correct selection in the Levin-Robbins sequential elimination procedure. Stat Sin 1999;9(3):879-91. |
| 11878656 | Background | Malviya S, Voepel-Lewis T, Tait AR, Merkel S, Tremper K, Naughton N. Depth of sedation in children undergoing computed tomography: validity and reliability of the University of Michigan Sedation Scale (UMSS). Br J Anaesth. 2002 Feb;88(2):241-5. doi: 10.1093/bja/88.2.241. |
| 19026467 | Background | Bhatt M, Kennedy RM, Osmond MH, Krauss B, McAllister JD, Ansermino JM, Evered LM, Roback MG; Consensus Panel on Sedation Research of Pediatric Emergency Research Canada (PERC) and the Pediatric Emergency Care Applied Research Network (PECARN). Consensus-based recommendations for standardizing terminology and reporting adverse events for emergency department procedural sedation and analgesia in children. Ann Emerg Med. 2009 Apr;53(4):426-435.e4. doi: 10.1016/j.annemergmed.2008.09.030. Epub 2008 Nov 20. |
| 3430286 | Background | Elliott CH, Jay SM, Woody P. An observation scale for measuring children's distress during medical procedures. J Pediatr Psychol. 1987 Dec;12(4):543-51. doi: 10.1093/jpepsy/12.4.543. No abstract available. |
| 40720114 | Result | Tsze DS, Woodward HA, McLaren SH, Leu CS, Venn AMR, Hu NY, Flores-Sanchez PL, Stefan BR, Shen ST, Ekladios MJ, Cravero JP, Dayan PS. Optimal Dose of Intranasal Midazolam for Procedural Sedation in Children: A Randomized Clinical Trial. JAMA Pediatr. 2025 Sep 1;179(9):979-986. doi: 10.1001/jamapediatrics.2025.2181. |
Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.3 mg/kg. Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. |
| BG002 | 0.4 mg/kg | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.4 mg/kg. Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. |
| BG003 | 0.5 mg/kg | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.5 mg/kg. Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Inter-Quartile Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.3 mg/kg.
Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device.
| OG002 | 0.4 mg/kg | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.4 mg/kg. Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. |
| OG003 | 0.5 mg/kg | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.5 mg/kg. Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. |
|
|
| Secondary | Time to Recovery | Time (in minutes) from procedure completion until a Simplified Aldrete Score (SAS) of at least 6 is achieved. The score ranges from 0 (lowest) to 8 (highest). If a patient already fulfills criteria for recovery at procedure start, then time to recovery is 0. | Posted | Median | Inter-Quartile Range | minutes | From study drug administration until patient discharge (approximately 120 minutes) |
|
|
|
| Secondary | Number of Adverse Events | Adverse events will be defined using the Pediatric Emergency Research Canada and Pediatric Emergency Care Applied Research Network Consensus-Based Recommendations. These adverse events include oxygen desaturation; apnea (central, obstructive, laryngospasm); clinically apparent pulmonary aspiration; retching/vomiting; bradycardia; hypotension; excitatory movements; paradoxical response to sedation; unpleasant recovery reactions; and permanent complications (including death). | Posted | Number | adverse events | From study drug administration until patient discharge (approximately 120 minutes) |
|
|
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| Secondary | Time to Onset of Minimal Sedation | Time (in minutes) from administration of intranasal midazolam until a University of Michigan Sedation State (UMSS) score of 1 is achieved. The UMSS represents a spectrum of depth of sedation ranging from unarousable (4) to awake and alert (0). Note: This outcome was initially listed as a primary outcome, but was changed to a secondary outcome in the IRB-approved protocol and prior to enrollment of the first patient. | Posted | Median | Inter-Quartile Range | minutes | From study drug administration until procedure finished (approximately 60 minutes) |
|
|
|
| Secondary | UMSS Scale Score | Depth of sedation will be measured using the University of Michigan Sedation Scale (UMSS). This sedation scale ranges from zero to four with higher numbers indicating deeper sedation. | Posted | Count of Participants | Participants | From study drug administration until procedure finished (approximately 60 minutes) |
|
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| 0 |
| 19 |
| 0 |
| 19 |
| 0 |
| 19 |
| EG001 | 0.3 mg/kg | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.3 mg/kg. Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. | 0 | 24 | 0 | 24 | 0 | 24 |
| EG002 | 0.4 mg/kg | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.4 mg/kg. Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. | 0 | 29 | 0 | 29 | 2 | 29 |
| EG003 | 0.5 mg/kg | Children in a single urban pediatric emergency department (ED) randomized to receive IN midazolam at 0.5 mg/kg. Intranasal midazolam: 5 mg/mL concentration of midazolam. Maximum dose = 10 mg. Administered using a mucosal atomization device. | 0 | 29 | 0 | 29 | 0 | 29 |
| Paradoxical reaction | Nervous system disorders | Systematic Assessment |
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| D006571 | Heterocyclic Compounds |
| UMSS = 1 |
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| UMSS = 2, 3 or 4 |
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