Maximizing trEatment of Neurological Dysfunction Using INtravenous Guanfacine Study (MENDING)

• ClinicalTrials.gov Identifier: NCT04742673
• Recruitment Status: Recruiting
• First Posted: February 8, 2021
• Last Update Posted: January 21, 2022
• Sponsor: Vanderbilt University Medical Center
• Collaborators: Massachusetts General Hospital; National Institute on Aging (NIA)
• Information provided by (Responsible Party): Christopher G Hughes, Vanderbilt University Medical Center

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Critical Illness; Delirium; Cognitive Impairment	Drug: Guanfacine; Drug: Placebo	Phase 2

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Maximizing trEatment of Neurological Dysfunction Using INtravenous Guanfacine Study
• Actual Study Start Date: May 4, 2021
• Estimated Primary Completion Date: June 30, 2023
• Estimated Study Completion Date: June 30, 2024

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Participants will flow through the trial in the following manner: Consent in ICU: perform required inclusion/exclusion assessments; discuss study goals, activities, and requirements; obtain informed consent; Pre-randomization phase: twice daily assessments of mental status; Randomize delirious patients: IV guanfacine or placebo; Interventional Trial phase: study drug administration, mental status assessments, safety monitoring; Blood draws: collect blood samples on Interventional Trial Phase days 1 and 2; Follow-up assessments: telephone and online questionnaires at 30, 90, and 180 days after hospital discharge.	Drug: Placebo; Patients randomized to the placebo arm will receive intravenous normal saline when they exhibit ICU delirium.
Experimental: IV Guanfacine; Participants will flow through the trial in the following manner: Consent in ICU: perform required inclusion/exclusion assessments; discuss study goals, activities, and requirements; obtain informed consent; Pre-randomization phase: twice daily assessments of mental status; Randomize delirious patients: IV guanfacine or placebo; Interventional Trial phase: study drug administration, mental status assessments, safety monitoring; Blood draws: collect blood samples on Interventional Trial Phase days 1 and 2; Follow-up assessments: telephone and online questionnaires at 30, 90, and 180 days after hospital discharge.	Drug: Guanfacine; Patients randomized to the IV Guanfacine arm will receive intravenous guanfacine when they exhibit ICU delirium.

Outcome Measures

Primary Outcome Measures :

1. Number of days alive without delirium or coma [ Time Frame: 14 days ]

Secondary Outcome Measures :

1. Days alive and free of mechanical ventilation [ Time Frame: 28 days ]
2. Days alive and free of the intensive care unit [ Time Frame: 28 days ]
3. Cognitive function [ Time Frame: up to 180 days after hospital discharge ]
   Telephone Montreal Cognitive Assessment

Other Outcome Measures:

1. Days alive and free of the hospital [ Time Frame: 28 days ]
2. Mortality [ Time Frame: up to 1 year ]
3. Physical Function [ Time Frame: up to 180 days after hospital discharge ]
   Patient-Reported Outcomes Measurement Information System V.1.2-Physical Function 8b
4. Global Health [ Time Frame: up to 180 days after hospital discharge ]
   Patient-Reported Outcomes Measurement Information System V.1.1-Global
5. Pain Interference [ Time Frame: up to 180 days after hospital discharge ]
   Patient-Reported Outcomes Measurement Information System V.1.0-Pain Interference 8a
6. Applied Cognition [ Time Frame: up to 180 days after hospital discharge ]
   Patient-Reported Outcomes Measurement Information System V.1.0-Applied Cognition
7. Sleep [ Time Frame: up to 180 days after hospital discharge ]
   Patient-Reported Outcomes Measurement Information System V.1.0-Sleep Disturbance
8. Co-administration of sedatives, analgesics, and antipsychotics [ Time Frame: up to 14 days ]
   Frequency and quantity of administration
9. Hypotension [ Time Frame: up to 14 days ]
   Refractory systolic blood pressure < 90 mm Hg or Mean arterial blood pressure < 65 mm Hg despite ongoing ICU therapies
10. Bradycardia [ Time Frame: up to 14 days ]
    Heart rate < 60 beats per minute despite ongoing ICU therapies
11. Mental status [ Time Frame: up to 14 days ]
    New, acute neurologic disturbances such as blurred vision, dizziness, weakness, or vertigo

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Christopher Hughes, MD; 6153436268; christopher.hughes@vumc.org

Locations

United States, Tennessee

Vanderbilt University Medical Center; Recruiting

Nashville, Tennessee, United States, 37212

Contact: Christopher G Hughes, MD 615-343-6268 christopher.hughes@vumc.org

Sponsors and Collaborators

Vanderbilt University Medical Center

Massachusetts General Hospital

National Institute on Aging (NIA)

Investigators

• Principal Investigator: Christopher Hughes, MD; Vanderbilt University Medical Center

More Information

• Responsible Party: Christopher G Hughes, Professor of Anesthesiology, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT04742673
• Other Study ID Numbers: U11543; 3R01AG053582-05S1 ( U.S. NIH Grant/Contract )
• First Posted: February 8, 2021
• Last Update Posted: January 21, 2022
• Last Verified: January 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Delirium; Critical Illness; Neurocognitive Disorders; Mental Disorders; Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Disease Attributes; Pathologic Processes; Guanfacine; Antihypertensive Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs