Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Pediatrics Subjects

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hospira, Inc.
ClinicalTrials.gov Identifier:
NCT00652028
First received: April 1, 2008
Last updated: August 7, 2015
Last verified: August 2015
  Purpose

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 Intervention Phase
Intubated and Mechanically Ventilated Pediatric Subjects
Drug: Dexmedetomidine, midazolam; fentanyl
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Hospira, Inc.:

Primary Outcome Measures:
  • 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. ] [ Designated as safety issue: No ]
    Area under the concentration-time curve from time zero to the time of the last measurable concentration (AUC0-t) for Dexmedetomidine

  • 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. ] [ Designated as safety issue: No ]
    Area under the concentration-time curve from time zero to the time infinity (AUC0-∞) for Dexmedetomidine

  • 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. ] [ Designated as safety issue: No ]
    Observed peak plasma concentration (Cmax) for Dexmedetomidine

  • 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. ] [ Designated as safety issue: No ]
    Terminal elimination half-life (t1/2) for Dexmedetomidine

  • 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. ] [ Designated as safety issue: No ]
    Plasma concentration at steady state (Css) for Dexmedetomidine

  • 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. ] [ Designated as safety issue: No ]
    Volume of steady state distribution (Vss) for Dexmedetomidine

  • 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. ] [ Designated as safety issue: No ]
    Clearance (CL) for Dexmedetomidine

  • 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. ] [ Designated as safety issue: No ]

    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.

  • Number of Subjects Who Received Rescue Medication for Sedation (Midazolam) and Analgesics (Fentanyl) [ Time Frame: During the treatment period (Approximately 24 hours) ] [ Designated as safety issue: Yes ]
    Number of subjects who received rescue medication for Sedation (Midazolam) and analgesics (Fentanyl) while intubated during Treatment Period


Enrollment: 69
Study Start Date: November 2008
Study Completion Date: April 2010
Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   2 Years to 16 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00652028

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, Inc.
  More Information

No publications provided

Responsible Party: Hospira, Inc.
ClinicalTrials.gov Identifier: NCT00652028     History of Changes
Other Study ID Numbers: DEX-08-01
Study First Received: April 1, 2008
Results First Received: March 11, 2015
Last Updated: August 7, 2015
Health Authority: United States: Food and Drug Administration
Guatemala: Ministry of Public Health and Social Assistance

Keywords provided by Hospira, Inc.:
Pharmacokinetics
Pharmacodynamics
Escalating dose
Dexmedotimidine
Intubated
Mechanically ventilated
Pediatrics

Additional relevant MeSH terms:
Dexmedetomidine
Adrenergic Agents
Adrenergic Agonists
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Analgesics
Analgesics, Non-Narcotic
Central Nervous System Agents
Central Nervous System Depressants
Hypnotics and Sedatives
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 31, 2015