Study Evaluating Safety and Efficacy of Dexmedetomidine (DEX) in Intubated and Mechanically Ventilated Pediatric Intensive Care Unit (PICU) Subjects

Sedation Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00875550
• Other study ID #: DEX-08-05
• Status: Completed
• Phase: Phase 3
• First received: March 31, 2009
• Last updated: July 23, 2015
• Start date: January 2010
• Est. completion date: January 2011

Study information

• Verified date: July 2015
• Source: Hospira, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health Canada
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 175
• Est. completion date: January 2011
• Est. primary completion date: January 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Month to 16 Years

Eligibility

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).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Sedation

Intervention

Drug:
• Dexmedetomidine
Study drug titrated up or down to maintain target UMSS range.
• Midazolam
Rescue medication for sedation according to UMSS scores
• Fentanyl
Rescue medication for pain based on UMSS scores
• Morphine
Rescue medication for pain based on UMSS scores.

Locations

Country	Name	City	State
Canada	Pediatric Intensive Care Unit, CHU Sainte-Justine	Montreal	Quebec
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	BC Children's Hospital	Vancouver	British Columbia
United States	Akron Children's Hospital Medical Center	Akron	Ohio
United States	F3900 C.S. Mott Hospital SPC 5211 Dept. of Anaesthesiology	Ann Arbor	Michigan
United States	The John Hopkins Medical Institutions, Anesthesia and Critical Care Medicine	Baltimore	Maryland
United States	Montefiore Medical Center	Bronx	New York
United States	Medical University of South Carolina (MUSC)	Charleston	South Carolina
United States	University of Virginia, Division of Pediatric Critical Care	Charlottesville	Virginia
United States	University of Chicago Comer Children's Hospital	Chicago	Illinois
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	Children's Medical Center Dallas	Dallas	Texas
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Duke University Medical Center, Department of Anesthesiology	Durham	North Carolina
United States	Joe Dimaggio Children's Hospital/Memorial Regional Hospital, Pediatric Intensive Care Unit	Hollywood	Florida
United States	Critical Care	Jacksonville	Florida
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Loma Linda University Medical Center, Pediatric Dept., Div. of Critical Care - PICU	Loma Linda	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Pediatric Critical Care	Los Angeles	California
United States	Kosair Charities Pediatric Clinical Research Unit, University of Louisville	Louisville	Kentucky
United States	Loyola University Medical Center	Maywood	Illinois
United States	Miami Children's Hospital	Miami	Florida
United States	University of Miami - Miller School of Medicine	Miami	Florida
United States	Advocate Lutheran General Children's Hospital	Park Ridge	Illinois
United States	Pensacola Research Consultants, Inc.	Pensacola	Florida
United States	Maricopa Medical Center	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Northwest Pediatric Critical Care, P.C. Legacy Emanuel Children's Hospital	Portland	Oregon
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Gilette Children's Speciality Healthcare	Saint Paul	Minnesota
United States	Dept. of Anesthesia, SUMC	Stanford	California
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Hospira, Inc.

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Clinical Score Level of Sedation 0 Awake/Alert; Minimally Sedated: Tired/sleepy, appropriate response to verbal conversation and/or sounds.; Moderately Sedated: Somnolent/sleeping, easily aroused with light tactile stimulation.; Deeply sedated: Deep sleep, arousable only with significant physical stimulation.; Unarousable	6 to 24 hours	Yes
Secondary	Absolute Time on Study Drug That the Subject is in a UMSS Range of 1 to 3 While Intubated		6 to 24 hours	Yes
Secondary	Absolute Time on Study Drug That the Subject is Out of the Target Sedation Range (UMSS <1 or >3) While Intubated		6 to 24 hours	Yes
Secondary	Total Amount of Rescue Medication Required for Sedation and Analgesia While Intubated		6 to 24 hours	Yes
Secondary	Time to First Dose of Rescue Medication for Sedation and Analgesia		6 to 24 hours	Yes
Secondary	Time to Successful Extubation		6 to 24 hours	Yes