Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Pediatrics Subjects

Study Overview
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Brief Summary
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The objective of this study is to characterize the pharmacokinetic and pharmacodynamic profile of dexmedetomidine administered as an intravenous loading dose followed by a continuous intravenous infusion in pediatric subjects ages ≥2 through <17 years old.

Detailed Description
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This is a phase II, open-label, multicenter, escalating dose study evaluating the pharmacokinetics and pharmacodynamics of dexmedetomidine in pediatric subjects. The study population consists of initially intubated and mechanically ventilated pediatric subjects, ages ≥2 through <17 years old, that require sedation in an intensive care setting for a minimum of 6 hours. Subjects will be divided into two groups based on age: Group I will consist of subjects ages ≥2 through <6 years old and Group II subjects age ≥6 through <17 years old. Within each group there will be four escalating dosing levels. Both groups can enroll simultaneously; however within each group, the next dose level cannot begin to enroll until all subjects have completed the previous dose level and the Data Safety Monitoring Board (DSMB) has approved enrollment to the next level. The level of sedation will be assessed using the Ramsay Sedation Scale (RSS). Based on these scores, and clinical judgment, additional sedation with midazolam will be administered according to the label. Pain will be assessed using the Faces, Legs, Arms, Cry & Consolability (FLACC) scale. Venous blood samples for pharmacokinetic analysis will be obtained at designated times. The pharmacodynamic and safety measures that will be monitored and the pharmacodynamic impact of dexmedetomidine on tracheal extubation will also be explored if subject is extubated within 24 hours.

Official Title
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A Phase II, Open-Label, Multicenter, Escalating Dose, Study to Determine Pharmacokinetic and Pharmacodynamic Profile of Dexmedetomidine in Pediatric Subjects Ages ≥ 2 Through < 17 Years Old

Conditions
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Intubated and Mechanically Ventilated Pediatric Subjects

Intervention / Treatment
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* Drug: Dexmedetomidine, midazolam; fentanyl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Initially intubated and mechanically ventilated pediatric subjects in an intensive care setting anticipated to require a minimum of 6 hours of continuous intravenous sedation. Age: subjects must fit into one of the following age ranges at screening: ≥2 years old through <6 years old ≥6 years old through <17 years old 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. Subject's parent(s) or legal guardian(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: Pediatric subjects with neurological conditions that prohibit an evaluation of sedation Diminished consciousness from increased intracranial pressure. Extensive brain surgery (surgery requiring intracranial pressure monitor). Diminished cognitive function per PI's discretion. Subjects with immobility from neuromuscular disease or continuous infusion of neuromuscular blocking agents. Weight <10 kg. Subjects with second degree or third degree heart block unless subject has a pacemaker or pacing wires. Hepatic impairment Serum glutamic pyruvic transaminase/Alanine aminotransferase (SGPT/ALT) >100 U/L Hypotension based on repeat assessments prior to starting study drug: Age ≥2 years old through ≤12 years old: systolic blood pressure (SBP) <80 mmHg Age >12 years old through <17 years old: SBP <90 mmHg Pre-existing bradycardia prior to starting study drug defined as: Age ≥2 years old through ≤6 years old: ≤70 beats per minute (bpm) Age >6 years old through ≤12 years old: ≤60 bpm Age >12 years old through ≤16 years old: ≤50 bpm Acute thermal burns involving more than 15 percent total body surface area. Subjects who have a known allergy to dexmedetomidine, midazolam (MDZ) or fentanyl. Subjects with a life expectancy that is <72 hours. Subjects that are expected to have hemodialysis (continuous hemofiltration) or peritoneal dialysis within 48 hours. Subjects who have been treated with α-2 agonists/antagonists within two weeks. Subjects with a spinal cord injury above T5. Subjects who have received another investigational drug within the past 30 days. Subjects on nicotine replacement therapy. Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of this clinical study.

Ages Eligible for Study
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Minimum Age: 2 Years
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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group 1<br>Dose level 1 | Drug: Dexmedetomidine, midazolam; fentanyl<br>* Dexmedetomidine for sedation; midazolam for rescue sedation according to label; fentanyl for rescue pain according to the label<br>|
| Other: Group 2<br>Dose level 2 | Drug: Dexmedetomidine, midazolam; fentanyl<br>* Dexmedetomidine for sedation; midazolam for rescue sedation according to label; fentanyl for rescue pain according to the label<br>|
| Other: Group 3<br>Dose level 3 | Drug: Dexmedetomidine, midazolam; fentanyl<br>* Dexmedetomidine for sedation; midazolam for rescue sedation according to label; fentanyl for rescue pain according to the label<br>|
| Other: Group 4<br>Dose level 4 | Drug: Dexmedetomidine, midazolam; fentanyl<br>* Dexmedetomidine for sedation; midazolam for rescue sedation according to label; fentanyl for rescue pain according to the label<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC0-t) | Area under the concentration-time curve from time zero to the time of the last measurable concentration (AUC0-t) for Dexmedetomidine | ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI. | 
| Area Under the Concentration-time Curve From Time Zero to the Time Infinity (AUC0-∞) | Area under the concentration-time curve from time zero to the time infinity (AUC0-∞) for Dexmedetomidine | ≤30 min prior to start of the loading dose (LD); 5 min before finishing the LD; 0.5,1,2&4 to 6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4&10 hrs after end of MI. | 
| Observed Peak Plasma Concentration | Observed peak plasma concentration (Cmax) for Dexmedetomidine | ≤30 min prior to start of the loading dose (LD); 5 min before finishing the LD; 0.5,1,2&4 to 6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4&10 hrs after end of MI. | 
| Terminal Elimination Half-life (t1/2) | Terminal elimination half-life (t1/2) for Dexmedetomidine | ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI. | 
| Plasma Concentration at Steady State (Css) | Plasma concentration at steady state (Css) for Dexmedetomidine | ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI. | 
| Volume of Steady State Distribution (Vss) | Volume of steady state distribution (Vss) for Dexmedetomidine | ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI. | 
| Clearance (CL) | Clearance (CL) for Dexmedetomidine | ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI. | 
| Level of Sedation Based on Average Ramsay Sedation Scale (RSS) Score | RSS Score range from 1 to 6: Patient is anxious and agitated or restless, or both. Patient is cooperative, orientated and tranquil. Patient responds to command only. Patient exhibits brisk response to light glabellar (between the eyebrows) tap or loud auditory stimulus. Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus. Patient exhibits no response to stimulus. | Prior to loading (Baseline), 5 and 10 min during the load, at start of maintenance infusion and every 15 min for 1 hour, hourly during the maintenance period, before and within 5 min after midazolam or fentanyl dose during the dexmedetomidine infusion. | 
| Number of Subjects Who Received Rescue Medication for Sedation (Midazolam) and Analgesics (Fentanyl) | Number of subjects who received rescue medication for Sedation (Midazolam) and analgesics (Fentanyl) while intubated during Treatment Period | During the treatment period (Approximately 24 hours) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, Pharmacodynamics, Escalating dose, Dexmedotimidine, Intubated, Mechanically ventilated, Pediatrics