A Safety and Efficacy Study of Dexmedetomidine in ICU Patients Requiring Continuous Sedation

A Phase 4, Randomized, Double-Blind, Multi-Center, Comparator Study Evaluating the Safety and Efficacy of Dexmedetomidine Compared to IV Midazolam in ICU Subjects Requiring Greater Than Twenty-Four Hours of Continuous Sedation

The purpose of this study is to evaluate the safety and efficacy of dexmedetomidine in ICU subjects who are initially intubated, mechanically ventilated and require sedation for beyond 24 hours.

Traditional agents such benzodiazepines and propofol have long been used to sedate critically ill patients. Unfortunately, these agents have serious disadvantages that may have a negative impact on patient outcomes. These disadvantages include respiratory depression, prolonged mechanical ventilation, paradoxical agitation, myocardial depression, hypotension, tachyphylaxis, physical dependence, and an unpredictable duration of action following long term infusions. Additionally, concomitant use of an opioid or other analgesic is often required for ICU patients to achieve adequate levels of pain relief, which may also prolong awakening and possibly increase respiratory depression.

Dexmedetomidine may offer a new treatment option that remedies many of the deficiencies of traditional sedatives. This agent would provide for accurate, titratable sedation and analgesia without the concurrent respiratory depression and accumulation common to other agents. It may permit greater patient interaction due to reduced impairment of cognition and may reduce risks associated with opioids due to its analgesia sparing property. Although such a drug may have important benefits for ICU patients requiring sedation for greater than 24 hours, dexmedetomidine is not currently approved for such long-term usage.

Inclusion Criteria:

1. Subject is ≥18 years of age.

2. If female, subject is non-lactating, and is either:

   1. Not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy.
   2. Of childbearing potential but is not pregnant as confirmed by negative serum pregnancy test at time of screening, and is practicing one of the following methods of birth control: oral or parenteral contraceptives for three months prior to study drug administration, a vasectomized partner, or abstinence from sexual intercourse.

3. Subject is initially intubated and mechanically ventilated, or is planned for imminent intubation and mechanical ventilation, sedation is anticipated to be required during mechanical ventilation, and mechanical ventilation is anticipated to continue for at least 72 hours.

4. Subject or subject's legally authorized representative has voluntarily signed and dated an informed consent form, approved by the applicable Institutional Review Board (IRB), after the nature of the study has been explained and the subject or subject's legally authorized representative has had the opportunity to ask questions. The informed consent must be signed before any study specific procedures are performed.

5. Subject is sedated within a Richmond Agitation-Sedation Scale (RASS) range of -2 to +1 at the time of initiation of study drug

Exclusion Criteria:

1. Subject has been intubated for greater than 96 hours prior to the initiation of study drug (thus, the attainment of consent, screening evaluations, and randomization must all have been completed by the 96th hour post-intubation, so that the actual initiation of the study drug infusion may start by the end of the 96 hour window).

2. Subject has serious central nervous system pathology/trauma that, per clinical judgment of the Investigator, precludes responsiveness or survival.

3. Subject for whom opiates, benzodiazepines, or dexmedetomidine are contraindicated, or who has known or suspected serious allergy to any drug that might be administered during the course of the study.

4. Subject for whom alpha-2 agonists are contraindicated.

5. Subject requires neuromuscular blocking agents during the study for use other than intubation.

6. Subject requires epidural or spinal analgesia during the study.

7. Subject meets any of the following cardiovascular criteria:

   • Acute unstable angina (defined during current hospital stay).
   • Suspicion of acute myocardial infarction.
   • Considered to have a left ventricular ejection fraction of less than 30%. Decision to exclude is predicated on the Investigator's opinion, and may be based on any combination of acute presentations, recently performed diagnostic studies, or a history that suggests poor cardiac function. Pulmonary congestion of a non-cardiac origin or mild congestive failure primarily attributable to etiologies other than poor ventricular function are not exclusion criteria.
   • Heart rate <50 bpm prior to infusion start.
   • Systolic blood pressure <90 mmHg prior to infusion start.
   • Conduction abnormalities except 1st degree AV block and rate-controlled atrial fibrillation; subjects with functional pacemaker capacity may be enrolled.

8. Subject is hospitalized primarily due to trauma and/or burns, has received general anaesthesia within the 24 hours prior to the start of study drug infusion, or is anticipated to require general anaesthesia within 24 hours after the start of the infusion.

9. Subject has participated in a trial with any experimental drug within 30 days prior to enrollment in the study, or has ever been enrolled in this study.

10. Subject is unable to undergo any procedure required by the protocol.

11. Subject has laboratory results indicating the presence of liver disease consistent with a Child-Pugh score >9 (Grade C).

12. Subject has acute hepatitis, history or presence of chronic hepatitis, and/or has had a positive result for Hepatitis B Surface Antigen Test.

13. Subject requires dialysis (eg, hemodialysis, peritoneal dialysis, Continuous Venovenous Hemodialysis [CVVHD]).

14. Subject has a known, uncontrolled seizure disorder.

15. Subject has, per the Investigator's judgment, a known or suspected physical or psychological dependence on an abused drug, other than alcohol.

16. Subject has a known psychiatric illness that could confound a normal response to sedative treatment.

17. Subject is incarcerated.

18. Subject is terminally ill with a life duration expectancy of ≤60 days.

19. Subject has any other condition or factor which, in the Investigator's opinion, might increase the risk to the subject.