Open-Label, Safety Study Evaluating the Use of Dexmedetomidine in Pediatric Subjects Undergoing Procedure-Type Sedation

Study Overview
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Brief Summary
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The objective of this study is to evaluate the safety of dexmedetomidine in a pediatric population requiring non-intubated, spontaneous breathing, moderate to deep sedation (NI-MDS) for elective diagnostic or therapeutic procedures, expected to take more than 30 minutes.

Detailed Description
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This study was designed to evaluate the safety of a continuous infusion of dexmedetomidine (1 mcg/kg loading dose with 0.6 mcg/kg/hr initial maintenance dose and titrated between 0.2-1.0 mcg/kg/hr) administered to subjects requiring non-intubated, spontaneous breathing, moderate to deep sedation (NI-MDS) for elective diagnostic or therapeutic procedures that are expected to take more than 30 minutes.

Official Title
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Phase IV, Open-Label, Safety Study Evaluating the Use of Dexmedetomidine in Pediatric Subjects Undergoing Procedure-Type Sedation

Conditions
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Ultrasound, CT Scans, MRIs

Intervention / Treatment
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* Drug: Dexmedetomidine
* Drug: Midazolam
* Drug: Fentanyl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is ≥28 weeks gestational age and <17 years of age. - Preterm subjects ≥28 weeks through <38 weeks, gestational age; (Note: Gestational age will be calculated as the time elapsed between the first day of the last menstrual period to the day of enrollment. If pregnancy was achieved using assisted reproductive technology, gestational age will be calculated by adding 2 weeks to the gestational age as calculated above.) Subject is American Society of Anesthesiologists (ASA) Physical Status I, II or III. Subject requires non-intubated, spontaneous breathing, moderate to deep sedation (NI-MDS) in an operating or procedure room with an an intensivist, anesthesiologist or dental anesthesiologist in attendance. Scheduled for an elective procedure that falls into one of the following three populations: Non-invasive diagnostic/therapeutic procedures (NIDTP): including ultrasound (US), computed tomography (CT) scans, magnetic resonance imaging (MRI), cardiac catheterization, transthoracic echocardiogram (TTE); Minimally invasive diagnostic/therapeutic procedures (MIDTP): including minimally invasive procedures performed under US or CT guidance (e.g. US or CT-guided solid organ biopsy), and routine myocardial biopsies in cardiac transplant recipients; Surgical procedures: including small surgical procedures (e.g. excisions, biopsies) and dental procedures (e.g. extractions, pulpectomy, pediatric rehabilitation dental procedures, filings and crowns). Duration of the procedure is expected to take at least 30 minutes to complete. If female, subject is non-lactating and is either: Not of childbearing potential, defined as pre-menarche, or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy or hysterectomy. Of childbearing potential but is not pregnant at time of baseline and is practicing one of the following methods of birth control: oral or parenteral contraceptives, double-barrier method, vasectomized partner, or abstinence from sexual intercourse. Subject's parent(s) or legally acceptable representative(s) has/have voluntarily signed and dated the informed consent document approved by the Institutional Review Board. Assent will be obtained where age-appropriate and according to state regulations. Exclusion Criteria: Subjects weight at the time of screening is less than 1000 g. Subject has received general anesthesia within 7 days prior to study drug administration. Subject has participated in an experimental/investigational drug study within 30 days prior to study drug administration. Subject has been exposed to dexmedetomidine within 48 hours prior to study drug administration. Subject that has been previously enrolled in this study (DEX-10-16). Subject requires endotracheal intubation or laryngeal mask airway (LMA). Subject is with neurological conditions that in the opinion of the Investigator will preclude reliable assessment of sedation scoring. Examples include, but are not limited to the following: cerebral palsy, autism, severe mental retardation, etc. Subject has central nervous system (CNS) disease with an anticipated potential for increased intracranial pressure, an uncontrolled seizure disorder and/or known psychiatric illness that could confound a normal response to sedative treatment. Subject requires epidural or spinal anesthesia. Subject has received treatment with an alpha-2 agonist or antagonist within 14 days prior to study drug administration. Subject has a known allergy to dexmedetomidine, midazolam or fentanyl. Subject is requiring cardiac catheterization for the purpose of conducting an electrophysiology (EP) evaluation or percutaneous intervention (i.e. angioplasty). Subject for whom opiates, benzodiazepines, dexmedetomidine or other alpha-2 agonists are contraindicated. Subject has received an IV opioid within one hour, or oral/intramuscular (PO/IM) opioid within four hours, prior to the start of study drug administration. Subject has received any pre-induction medication (ie, ketamine, chloral hydrate, benzodiazepines) within 4 hours prior to the start of study drug administration. Subject has acute myocardial infarction recently diagnosed by confirmatory laboratory findings within 6 weeks of screening. Subject has moderate to severe sleep apnea syndrome. Subject has oxygen saturation (SpO2) ≤90% at screening or baseline, except for patients with known cyanotic heart disease undergoing cardiac catheterization. Subject has bradycardia immediately before dosing, according to respective age group. ≥28 weeks to <1 month: Heart Rate (HR) <120 beats per minute (bpm) 1 month to <3 months: HR <100 bpm 3 months to <6 months: HR <90 bpm 6 months to <1 year: HR <80 bpm 1 year to <2 years: HR <70 bpm 2 years to <6 years: HR <60 bpm 6 years to <12 years: HR <55 bpm 12 years to 17 years: HR <50 bpm; Note: Subject can be reassessed after 5 minutes Subject has hypotension immediately before dosing, according to respective age group. ≥28 weeks to <1 month: <60 mmHg (systolic blood pressure [SBP]) 1 month to <12 months: <70 mmHg (SBP) 1 year to <10 years: <70 + (2 X age in years) mmHg (SBP) 10 years to 17 years: <90 mmHg (SBP); Note: Subject can be reassessed after 5 minutes Subject has a presence of second-degree or third-degree heart block at screening or baseline. The presence of a temporary or permanent pacemaker will waive this exclusion criterion. Subject has acute febrile illness, with a temperature (core or tympanic) ≥38.0°C. Subject has any other condition or factor which, in the Investigator's opinion, might increase the risk to the subject.

Ages Eligible for Study
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Minimum Age: 28 Weeks
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexmedetomidine<br> | Drug: Dexmedetomidine<br>* 0.1 - 1.0 mcg/kg/hr IV<br>Drug: Midazolam<br>* 0.025 - 2 mg/kg IV<br>Drug: Fentanyl<br>* 0.5 - 3 mcg/kg IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Who Had Success in Sedation | Success in sedation was defined by a combined endpoint which was the combination of the following: Subject had adequate level of sedation (University of Michigan Sedation Scale [UMSS] score between 1 to 3 [minimally sedated to deeply sedated] or Neonatal Pain, Agitation and Sedation Scale [N-PASS] score between -5 to -2 [Light sedation]) at least 80% of the time the subject was given the study drug. Subject had successfully completed the procedure without a need for rescue sedation (Midazolam). Subject had undergone the procedure without artificial ventilation or intervention to restore baseline or normal hemodynamic status | From baseline to end of post-treatment period (approximately 24 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Not Receiving Rescue Midazolam | Number of subjects who did not receive any rescue midazolam for sedation during the study drug infusion. | During the treatment period, up to approximately 24 hours | 
| Number of Subjects Who Have Undergone Procedures Without Artificial Ventilation or Intervention |  | During the treatment period, up to approximately 24 hours | 
| Number of Subjects Who Were Adequately Sedated at Least 80% of Time | Subjects who are adequately sedated (UMSS score of 1 to 3 or NPASS score of -5 to -2) at least 80% of the time sedated with the study drug | During the treatment period, up to approximately 24 hours | 
| Time to First Dose of Rescue Midazolam From Start of Dexmedetomidine Infusion | Kaplan-Meier estimates of time in minutes to first dose of rescue midazolam from onset of study drug infusion | During the treatment period, up to approximately 24 hours | 
| Frequency of Midazolam Required for Sedation | Frequency of rescue sedation (midazolam) required to maintain a subject within the target sedation range (UMSS score greater than 1 or N-PASS score less than -2). | During the treatment period, up to approximately 24 hours | 
| Frequency of Fentanyl Use for Analgesia | Frequency of rescue analgesia (fentanyl) required from the start of IV sedation to completion of the procedure. | During the treatment period, up to approximately 24 hours | 
| Total Amount of Rescue Sedation (Midazolam) | Total amount of rescue sedation (midazolam) required from the start of IV sedation to completion of the procedure | During the treatment period, up to approximately 24 hours | 
| Total Amount of Rescue Analgesia (Fentanyl) | Total amount of rescue analgesia (fentanyl) required from the start of IV sedation to completion of the procedure | During the treatment period, up to approximately 24 hours | 
| Number of Subjects Converted to Alternative Sedation or Anesthetic Therapy Due to Failure of Treatment of Study Drug and Rescue Medication |  | During the treatment period, up to approximately 24 hours |