Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Pediatrics Subjects

• ClinicalTrials.gov Identifier: NCT00652028
• Recruitment Status: Completed
• First Posted: April 3, 2008
• Results First Posted: August 14, 2015
• Last Update Posted: April 13, 2017
• Sponsor: Hospira, now a wholly owned subsidiary of Pfizer
• Information provided by (Responsible Party): Hospira, now a wholly owned subsidiary of Pfizer

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Intubated and Mechanically Ventilated Pediatric Subjects	Drug: Dexmedetomidine, midazolam; fentanyl	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 69 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: November 2008
• Actual Primary Completion Date: April 2010
• Actual Study Completion Date: April 2010

Arms and Interventions

Arm	Intervention/treatment
Group 1; Dose level 1	Drug: Dexmedetomidine, midazolam; fentanyl; Dexmedetomidine for sedation; midazolam for rescue sedation according to label; fentanyl for rescue pain according to the label
Group 2; Dose level 2	Drug: Dexmedetomidine, midazolam; fentanyl; Dexmedetomidine for sedation; midazolam for rescue sedation according to label; fentanyl for rescue pain according to the label
Group 3; Dose level 3	Drug: Dexmedetomidine, midazolam; fentanyl; Dexmedetomidine for sedation; midazolam for rescue sedation according to label; fentanyl for rescue pain according to the label
Group 4; Dose level 4	Drug: Dexmedetomidine, midazolam; fentanyl; Dexmedetomidine for sedation; midazolam for rescue sedation according to label; fentanyl for rescue pain according to the label

Outcome Measures

Primary Outcome Measures :

1. Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC0-t) [ Time Frame: ≤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 of the last measurable concentration (AUC0-t) for Dexmedetomidine
2. Area Under the Concentration-time Curve From Time Zero to the Time Infinity (AUC0-∞) [ Time Frame: ≤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. ]
   Area under the concentration-time curve from time zero to the time infinity (AUC0-∞) for Dexmedetomidine
3. Observed Peak Plasma Concentration [ Time Frame: ≤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 (Cmax) for Dexmedetomidine
4. Terminal Elimination Half-life (t1/2) [ Time Frame: ≤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. ]
   Terminal elimination half-life (t1/2) for Dexmedetomidine
5. Plasma Concentration at Steady State (Css) [ Time Frame: ≤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) for Dexmedetomidine
6. Volume of Steady State Distribution (Vss) [ Time Frame: ≤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) for Dexmedetomidine
7. Clearance (CL) [ Time Frame: ≤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) for Dexmedetomidine
8. Level of Sedation Based on Average Ramsay Sedation Scale (RSS) Score [ Time Frame: 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. ]

   RSS Score range from 1 to 6:

   1. Patient is anxious and agitated or restless, or both.
   2. Patient is cooperative, orientated and tranquil.
   3. Patient responds to command only.
   4. Patient exhibits brisk response to light glabellar (between the eyebrows) tap or loud auditory stimulus.
   5. Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus.
   6. Patient exhibits no response to stimulus.
9. Number of Subjects Who Received Rescue Medication for Sedation (Midazolam) and Analgesics (Fentanyl) [ Time Frame: During the treatment period (Approximately 24 hours) ]
   Number of subjects who received rescue medication for Sedation (Midazolam) and analgesics (Fentanyl) while intubated during Treatment Period

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 16 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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:

  1. Not of childbearing potential, defined as pre-menarche, or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy or hysterectomy.
  2. 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.

Contacts and Locations

Locations

United States, Florida

Miami Children's Hospital

Miami, Florida, United States, 33155

United States, Kentucky

University of Louisville/Kosair Children's Hospital

Louisville, Kentucky, United States, 40202

United States, New York

Women and Children's Hospital of Buffalo

Buffalo, New York, United States, 14222

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

United States, Ohio

University Hospitals Medical Center

Cleveland, Ohio, United States, 44106

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15213

United States, Virginia

Virginia Commonwealth University

Richmond, Virginia, United States, 23219

Guatemala

Unidad Cirugia Cardiovascular de Guatemala

Guatemala City, Guatemala

Sponsors and Collaborators

Hospira, now a wholly owned subsidiary of Pfizer

More Information

• Responsible Party: Hospira, now a wholly owned subsidiary of Pfizer
• ClinicalTrials.gov Identifier: NCT00652028
• Other Study ID Numbers: DEX-08-01
• First Posted: April 3, 2008
• Results First Posted: August 14, 2015
• Last Update Posted: April 13, 2017
• Last Verified: August 2015

Keywords provided by Hospira, now a wholly owned subsidiary of Pfizer:

Pharmacokinetics; Pharmacodynamics; Escalating dose; Dexmedotimidine; Intubated; Mechanically ventilated; Pediatrics

Additional relevant MeSH terms:

Fentanyl; Midazolam; Dexmedetomidine; Hypnotics and Sedatives; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; GABA Modulators; GABA Agents