Clinical trial NCT00875550: Study Evaluating Safety and Efficacy of Dexmedetomidine (DEX) in Intubated and Mechanically Ventilated Pediatric Intensive Care Unit (PICU) Subjects
Official title: A Phase III Randomized, Double-blind, Dose-Controlled, Multicenter Study Evaluating the Safety and Efficacy of Dexmedetomidine in Intubated and Mechanically Ventilated Pediatric Intensive Care Unit Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Sedation
Keywords: Intubated and mechanically ventilated PICU subjects
Lead sponsor: Hospira, now a wholly owned subsidiary of Pfizer
Sponsor class: INDUSTRY
First posted: 2009-04-03
Enrollment: 175
Sex: ALL
Minimum age (years): 1
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety and efficacy of dexmedetomidine (DEX) in intubated and mechanically ventilated pediatric intensive care unit (PICU) subjects. The key study objectives are:

* To characterize the loading and maintenance dosing of DEX by age group and overall medical condition of pediatric subjects
* To evaluate the safety and efficacy of loading and maintenance infusions for sedation in initially intubated and mechanically ventilated PICU subjects
* To explore the exposure-response relationship between dose of DEX and clinical measures of sedation and safety

Detailed description: An estimated 175 subjects will be enrolled at approximately 40 investigative sites. Subjects will be divided into two treatment groups to receive either high dose or low dose Dexmedetomidine (DEX). The loading and maintenance doses in both groups will be stratified according to the presence or absence of cardiopulmonary bypass. The level of sedation will be assessed using the University of Michigan Sedation Scale (UMSS). Score 0 (awake/alert); Score 1 (sleepy/responds appropriately); Score 2 (somnolent/arouses to light stimuli); Score 3 (deep sleep/arouses to deeper); Score 4 (unarousable to stimuli).

Based on these scores and clinical judgment, additional sedation with intravenous midazolam will be administered according to the label. The UMSS scores must be documented before the administration of every midazolam (MDZ) dose and within five minutes after each dose of MDZ. Fentanyl or morphine may be administered to treat pain. Subjects may be extubated after beginning of study drug but are not required to be as part of the study.

The efficacy and safety parameters that will be monitored include sedation levels, heart rate, blood pressure and ventilation indicators. Once subjects have met site-specified respiratory criteria, they will undergo tracheal extubation. The dexmedetomidine infusion may be continued during and after extubation if further sedation is required post-extubation. The continuous infusion of dexmedetomidine must be administered for a minimum of 6 hours and a maximum of 24 hours. Sedation levels, heart rate, blood pressure, respiratory rate, ventilator settings, SpO2 and if available transcutaneous carbon dioxide (TcCO2) and/or arterial blood gases (ABG) will be monitored and recorded in the peri-extubation period.

Eligibility criteria: Inclusion Criteria:

1. Initially intubated and mechanically ventilated pediatric subjects (≥1 month \[birth age corrected for prematurity\] to \<17 years of age) in an intensive care setting. The means by which the subject is intubated may include nasotracheal, endotracheal or via tracheotomy. The subject must be mechanically ventilated prior to and during the commencement of study drug.
2. Anticipated to require a minimum of 6 hours of continuous intravenous sedation.
3. American Society of Anesthesiologists (ASA) classification of 1, 2, 3 or 4.
4. A UMSS score of 1, 2, 3 or 4 at the start of infusion of study drug.
5. A dose has been established for this subject's age based upon the diagnosis procedures.

   Status post cardiopulmonary bypass (s/p CPB):
   * Low dose group: Loading dose: 0.2 mcg/kg Maintenance dose titration range (0.025-0.5 mcg/kg/hr)
   * High dose group: Loading dose: 0.5 mcg/kg Maintenance dose titration range (0.1-0.7 mcg/kg/hr)

   All other diagnoses:
   * Low dose group: Loading dose: 0.3 mcg/kg Maintenance dose titration range (0.05- 0.5mcg/kg/hr)
   * High dose group: Loading dose: 0.6 mcg/kg Maintenance dose titration range (0.2 - 1.4 mcg/kg/hr)
6. 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.
7. 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:

1. Pediatric subjects with neurological conditions that prohibit an evaluation of sedation in the opinion of the investigator (e.g. increased intracranial pressure or extensive brain surgery).
2. The infusion pump minimal capacity cannot accommodate the lowest possible maintenance infusion rate of study drug based on subject's weight.
3. Subjects with second degree or third degree heart block unless subject has a pacemaker or pacing wires.
4. Hypotension that persist beyond a 15 min of re-assessments prior to starting study drug:

   * Age 1 month to ≤6 months old: systolic blood pressure (SBP) \<60 (millimeters of mercury) mmHg
   * Age \>6 months to \<2 yrs old: SBP \<70 mmHg
   * Age \>2 to \<12 yrs old: SBP \<80 mmHg
   * Age \>12 to \<17 yrs old: SBP \<90 mmHg
5. Pre-existing bradycardia that persists beyond a 15 min period of re-assessment prior to starting study drugs:

   * Age 1 month to \<2 months old: HR \<90 beats per min (bpm)
   * Age ≥2 months to \<12 months old: HR \<80 bpm
   * Age ≥12 months to \<2 yrs old: HR \<70 bpm
   * Age ≥ 2 to \<12 yrs old: HR \<60 bpm
   * Age ≥ 12 to \<17 yrs old: HR \<50 bpm
6. Serum glutamic pyruvic transaminase (SGPT)/alanine aminotransferase (ALT): 1 month -12 months: \>165 U/L; \>12 months to \<17 years: ≥100 U/L.

   Note: Subjects may be rescreened up to 6 hrs prior to study drug infusion (not including subjects undergoing cardiac surgery with CPB).
7. Subjects who have a known allergy to dexmedetomidine, MDZ, morphine or fentanyl.
8. Requirement for medications other than DEX, midazolam, morphine or fentanyl for sedation and pain control.
9. Subjects with immobility form neuromuscular disease, paralysis from administration of neuromuscular blocking agents, spinal cord injury above T5, or subjects with muscle weakness form congenital or systemic medical illness etiologies. Note: subjects who received NMB agents intraoperatively must be, in the Investigator's opinion, free of residual neuromuscular blockade prior to dosing with study drug.
10. Subjects who have received another investigational drug or device within the past 30 days.
11. Subjects who have received DEX in a previous investigational trial within the previous 12 weeks.
12. Subjects who, in the opinion of the investigator, have any other condition where the risks of DEX would be expected to outweigh its benefits (e.g. cardiogenic shock on \>2 vasopressors).
13. Subjects who will require alpha-2 agonists/antagonists listed below within 48 hrs prior to baseline.

Alpha-2 Agonists: Xylazine\*, Clonidine (Catapres, Dixarit), Guanfacine (Tenex), Guanabenz (Wytensin), Mivazerol, Guanadrel (Hylorel), Guanethidine (Ismelin) and Methyldopa (Aldomet). \* Xylazine is a veterinary product, but has abuse potentIal in humans.

Alpha-2 Antagonists: Corynanthine, Phenoxybenzamine (Dibenzyline), Phentolamine (Regitine, Rogitine), Tolazoline (Priscoline), Yohimbine, Rauwolscine, Idazoxan, Reserpine (Serpasil) and Mirtazapine (Remeron, Remeron Soltab).

Primary outcomes:
measure: Percentage of Subjects That do Not Require Rescue Midazolam (MDZ) for Sedation Based on Achieving and Maintaining a Target University of Michigan Sedation Scale (UMSS) Score of 1 to 3 While Intubated.
timeFrame: 6 to 24 hours
Secondary outcomes:
measure: Absolute Time on Study Drug That the Subject is in a UMSS Range of 1 to 3 While Intubated
timeFrame: 6 to 24 hours
measure: Absolute Time on Study Drug That the Subject is Out of the Target Sedation Range (UMSS <1 or >3) While Intubated
timeFrame: 6 to 24 hours
measure: Total Amount of Rescue Medication Required for Sedation and Analgesia While Intubated
timeFrame: 6 to 24 hours
measure: Time to First Dose of Rescue Medication for Sedation and Analgesia
timeFrame: 6 to 24 hours
measure: Time to Successful Extubation
timeFrame: 6 to 24 hours
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Maricopa Medical Center
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center, Pediatric Dept., Div. of Critical Care - PICU
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: Pediatric Critical Care
state: California
city: Stanford
country: United States
facility: Dept. of Anesthesia, SUMC
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Hollywood
country: United States
facility: Joe Dimaggio Children's Hospital/Memorial Regional Hospital, Pediatric Intensive Care Unit
state: Florida
city: Jacksonville
country: United States
facility: Critical Care
state: Florida
city: Miami
country: United States
facility: University of Miami - Miller School of Medicine
state: Florida
city: Miami
country: United States
facility: Miami Children's Hospital
state: Florida
city: Orlando
country: United States
state: Florida
city: Pensacola
country: United States
facility: Pensacola Research Consultants, Inc.
state: Florida
city: Chicago
country: United States
facility: University of Chicago Comer Children's Hospital
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Park Ridge
country: United States
facility: Advocate Lutheran General Children's Hospital
state: Illinois
city: Louisville
country: United States
facility: Kosair Charities Pediatric Clinical Research Unit, University of Louisville
state: Kentucky
city: Baltimore
country: United States
facility: The John Hopkins Medical Institutions, Anesthesia and Critical Care Medicine
state: Maryland
city: Ann Arbor
country: United States
facility: F3900 C.S. Mott Hospital SPC 5211 Dept. of Anaesthesiology
state: Michigan
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Saint Paul
country: United States
facility: Gilette Children's Speciality Healthcare
state: Minnesota
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center, Department of Anesthesiology
state: North Carolina
city: Akron
country: United States
facility: Akron Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Portland
country: United States
facility: Northwest Pediatric Critical Care, P.C. Legacy Emanuel Children's Hospital
state: Oregon
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina (MUSC)
state: South Carolina
city: Dallas
country: United States
facility: Children's Medical Center Dallas
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia, Division of Pediatric Critical Care
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Madison
country: United States
state: Wisconsin
city: Vancouver
country: Canada
facility: BC Children's Hospital
state: British Columbia
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Pediatric Intensive Care Unit, CHU Sainte-Justine
state: Quebec
Study officials:
affiliation: Medical Director, Hospira
name: Robert Bilkovski, MD
role: STUDY_DIRECTOR
References: