Maximizing trEatment of Neurological Dysfunction Using INtravenous Guanfacine Study

Critical Illness Clinical Trial

— MENDING  

Official title:

Maximizing trEatment of Neurological Dysfunction Using INtravenous Guanfacine Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04742673
• Other study ID #: U11543
• Secondary ID: 3R01AG053582-05S
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: May 4, 2021
• Est. completion date: December 31, 2025

Study information

• Verified date: April 2024
• Source: Vanderbilt University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This proof-of-concept study examines whether the acute brain dysfunction that occurs in critically ill patients is improved by administration of intravenous guanfacine.

Description:

Delirium during critical illness is, to date, the primary potentially modifiable risk factor for acquired dementia after critical illness (ADRD). There are, however, no Food and Drug Administration (FDA) approved medications to mitigate delirium. Benzodiazepines are ineffective at reducing the incidence or duration of delirium, and on the contrary, increase the risk. Furthermore, large randomized controlled studies have shown that antipsychotic agents have no effect (vs. placebo) on delirium duration, mechanical ventilation, hospital length of stay, or death. Therefore, current clinical practice guidelines no longer recommend routine use of benzodiazepines or antipsychotics for treatment of delirium. Despite these recommendations, benzodiazepine, antipsychotics, and other drugs are routinely prescribed to critically ill patients due to the urgent clinical need to control delirium symptoms. The alpha-2 agonist dexmedetomidine is the most successful agent for delirium identified to date. However, it is typically administered as a continuous infusion and requires ICU-level monitoring due to hypotension and bradycardia risks. The delirium sparing benefits of dexmedetomidine have been postulated to result from alpha-2 agonist mediated modulation of CNS inflammation, microcirculatory blood flow, and biomimetic sleep.

The alpha-2 agonist guanfacine, an FDA-approved medication for use in hypertension and attention deficit hyperactivity disorder, has a higher selectivity for the alpha-2A receptor in the central nervous system. Thus, delirium sparing benefits may be improved with guanfacine while reducing systemic effects. Further, instead of a continuous infusion, the pharmacokinetic and pharmacodynamic properties of guanfacine favor a twice a day bolus dosing schedule. This Maximizing trEatment of Neurological Dysfunction using INtravenous Guanfacine (MENDING) study will investigate the benefits of intravenous (IV) guanfacine. In this phase II proof-of-concept trial of IV guanfacine vs. placebo for the treatment of critical illness delirium, the following specific aims will be tested in critically ill patients with delirium:

Aim 1: To determine whether IV guanfacine will increase the number of days alive without delirium and coma (DCFDs) over 14 days relative to placebo.

Aim 2: To evaluate whether IV guanfacine twice a day will increase days alive and free of mechanical ventilation (VFDs) and days alive and free of the ICU (IFDs) over 28 days relative to placebo.

Aim 3: To assess whether IV guanfacine can reduce the development of ADRD after critical illness.

Identifying a safe and effective treatment for delirium would have exponential benefits to patients, families, healthcare, and society. This first study of IV guanfacine builds upon extensive research regarding the benefits of alpha-2 agonists for brain dysfunction.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 46
• Est. completion date: December 31, 2025
• Est. primary completion date: March 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. adult patients (= 18 years old)

2. requiring admission to an ICU

3. for treatment of respiratory failure (e.g., mechanical ventilation, non-invasive positive pressure ventilation [NIPPV], Extracorporeal Membrane Oxygenation [ECMO], optiflow) and/or for treatment of shock (e.g., vasopressors, ECMO, intra-aortic balloon pump [IABP]).

Exclusion Criteria:

1. allergic to guanfacine, clonidine, or dexmedetomidine

2. on home antipsychotics who, therefore, require continuing antipsychotic administration in the hospital

3. present history of 2nd or 3rd degree heart block, or persistent bradycardia < 50 beats/minute that requires intervention (e.g., atropine, glycopyrrolate). If patient has a pacemaker for bradyarrythmias, then patient does not meet this exclusion criterion and may be enrolled.

4. co-enrolled in another interventional trial examining similar outcomes or in a study that does not allow co-enrollment

5. expected death within 24 hours of enrollment or lack of commitment to aggressive treatment by family or the medical team (e.g., likely withdrawal of life support measures within 24 hours of screening)

6. acute or subacute neurologic deficit that is expected to make the patient incapable of living independently after hospital discharge due to cognitive deficits (e.g., stroke, intracranial hemorrhage, cranial trauma, intracranial malignancy, anoxic brain injury, cerebral edema).

7. dementia or other chronic neurologic disease or disorder that makes the patient incapable of living independently at baseline

8. active substance abuse, psychotic disorder, or homelessness without a secondary contact person (which would make long-term follow-up difficult)

9. blindness or deafness (which would prevent assessment of the study's outcomes)

10. pregnancy or breastfeeding

11. prisoner

12. inability to start informed consent process within 72 hours from the time that all inclusion criteria were met

13. Cardiac surgery within the current hospitalization.

Related Conditions & MeSH terms

• Cognitive Impairment
• Critical Illness
• Delirium

Intervention

Drug:
• Guanfacine
Patients randomized to the IV Guanfacine arm will receive intravenous guanfacine when they exhibit ICU delirium.
• Placebo
Patients randomized to the placebo arm will receive intravenous normal saline when they exhibit ICU delirium.

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (3)

Lead Sponsor	Collaborator
Vanderbilt University Medical Center	Massachusetts General Hospital, National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Days alive and free of the hospital		28 days
Other	Mortality		up to 1 year
Other	Physical Function	Patient-Reported Outcomes Measurement Information System V.1.2-Physical Function 8b	up to 180 days after hospital discharge
Other	Global Health	Patient-Reported Outcomes Measurement Information System V.1.1-Global	up to 180 days after hospital discharge
Other	Pain Interference	Patient-Reported Outcomes Measurement Information System V.1.0-Pain Interference 8a	up to 180 days after hospital discharge
Other	Applied Cognition	Patient-Reported Outcomes Measurement Information System V.1.0-Applied Cognition	up to 180 days after hospital discharge
Other	Sleep	Patient-Reported Outcomes Measurement Information System V.1.0-Sleep Disturbance	up to 180 days after hospital discharge
Other	Co-administration of sedatives, analgesics, and antipsychotics	Frequency and quantity of administration	up to 14 days
Other	Hypotension	Refractory systolic blood pressure < 90 mm Hg or Mean arterial blood pressure < 65 mm Hg despite ongoing ICU therapies	up to 14 days
Other	Bradycardia	Heart rate < 60 beats per minute despite ongoing ICU therapies	up to 14 days
Other	Mental status	New, acute neurologic disturbances such as blurred vision, dizziness, weakness, or vertigo	up to 14 days
Primary	Number of days alive without delirium or coma		14 days
Secondary	Days alive and free of mechanical ventilation		28 days
Secondary	Days alive and free of the intensive care unit		28 days
Secondary	Cognitive function	Telephone Montreal Cognitive Assessment	up to 180 days after hospital discharge