Study Evaluating Safety and Efficacy of Dexmedetomidine (DEX) in Intubated and Mechanically Ventilated Pediatric Intensive Care Unit (PICU) Subjects
Condition: Sedation
Intervention: Dexmedetomidine; Midazolam; Fentanyl; Morphine
Intervention description: Study drug titrated up or down to maintain target UMSS range.; Rescue medication for sedation according to UMSS scores; Rescue medication for pain based on UMSS scores; Rescue medication for pain based on UMSS scores.
Intervention MeSH terms: Midazolam; Fentanyl; Dexmedetomidine; Morphine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 175.0
Sex: All
Minimum age: 1 Month
Maximum age: 16 Years
Healthy volunteers: No
Keywords: Intubated and mechanically ventilated PICU subjects

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
    

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).