A Phase 2 interventional study of Guanfacine and Placebo in Critical Illness, Delirium and Cognitive Impairment, sponsored by Vanderbilt University Medical Center. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-02-19.
Sponsored by Vanderbilt University Medical Center · Phase 2, Interventional, and Treatment
This proof-of-concept study examines whether the acute brain dysfunction that occurs in critically ill patients is improved by administration of intravenous guanfacine.
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.
1,881 studies on the registry are indexed under Critical Illness; 462 are open to participants now.
This study's enrollment of 46 is below the median of 90 across 979 interventional studies indexed under Critical Illness.
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Of its 122 completed or terminated interventional studies of FDA-regulated products, 91 (75%) have results posted.
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Exclusion Criteria:
Participants will flow through the trial in the following manner: 1. Consent in ICU: perform required inclusion/exclusion assessments; discuss study goals, activities, and requirements; obtain informed consent 2. Pre-randomization phase: twice daily assessments of mental status 3. Randomize delirious patients: IV guanfacine or placebo 4. Interventional Trial phase: study drug administration, mental status assessments, safety monitoring 5. Blood draws: collect blood samples on Interventional Trial Phase days 1 and 2 6. Follow-up assessments: telephone and online questionnaires at 30, 90, and 180 days after hospital discharge.
Drug: Placebo
Participants will flow through the trial in the following manner: 1. Consent in ICU: perform required inclusion/exclusion assessments; discuss study goals, activities, and requirements; obtain informed consent 2. Pre-randomization phase: twice daily assessments of mental status 3. Randomize delirious patients: IV guanfacine or placebo 4. Interventional Trial phase: study drug administration, mental status assessments, safety monitoring 5. Blood draws: collect blood samples on Interventional Trial Phase days 1 and 2 6. 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.
Patients randomized to the placebo arm will receive intravenous normal saline when they exhibit ICU delirium.
Number of Days Alive Without Delirium or Coma
Time frame: 14 days after randomization
Days Alive and Free of Mechanical Ventilation
Time frame: 28 days after randomization
Days Alive and Free of the Intensive Care Unit
Time frame: 28 days after randomization
Cognitive Function
Telephone Montreal Cognitive Assessment has a minimum score of 0 and a maximum score of 22, with higher numbers indicating better cognition. A score of 18 or below is considered a positive screen for at least mild cognitive impairment.
Time frame: 180 days after randomization
Days Alive and Free of the Hospital
Time frame: 28 days after randomization
Mortality
Time frame: 90 days after randomization
Physical Function
Patient-Reported Outcomes Measurement Information System V.1.2-Physical Function 8b is a process that involves using a specific set of 8 questions to assess a patient's self-reported ability to perform physical activities. These questions are designed to measure a person's physical function, focusing on their ability to perform daily activities, including those involving upper and lower extremities, and central body regions. Patients respond to each question on a scale, typically a five-point scale (e.g., 1 = not at all to 5 = completely). The total raw score is then converted to a T-score using a table provided in the PROMIS scoring manual. T-scores are standardized scores with a mean of 50 and a standard deviation of 10, allowing for comparison across individuals and populations. Higher T-scores generally indicate a higher level of physical function.
Time frame: 180 days after after randomization
Global Health
Patient-Reported Outcomes Measurement Information System V.1.1-Global is a 10-item questionnaire that measures physical and mental health in patients. The questionnaire uses a T-score metric, where a score of 50 represents the average for the US population with a standard deviation of 10. Higher T-scores indicate better health.
Time frame: 180 days after after randomization
Pain Interference
Patient-Reported Outcomes Measurement Information System V.1.0-Pain Interference 8a measures the self-reported consequences of pain on relevant aspects of a person's life and may include the extent to which pain hinders engagement with social, cognitive, emotional, physical, and recreational activities. It consists of 8 questions, each with a scale ranging from 1 (Not at all) to 5 (Very much). The score is calculated by summing the responses to all 8 questions, resulting in a raw score range from 8 to 40. This raw score is then converted into a T-score, with a mean of 50 and a standard deviation of 10, and a higher T-score indicating more pain interference.
Time frame: 180 days after randomization
Applied Cognition
Patient-Reported Outcomes Measurement Information System V.1.0-Applied Cognition is designed to assess a patient's self-perceived cognitive abilities and concerns in everyday life. The PROMIS measures use a T-score metric with a mean of 50 and a standard deviation of 10, where higher scores indicate better perceived cognitive functioning.
Time frame: 180 days after randomization
Sleep
Patient-Reported Outcomes Measurement Information System V.1.0-Sleep Disturbance utilizes a 5-point Likert scale to assess sleep quality, with higher scores indicating greater sleep disturbance. The scale's T-score is a standardized score with a mean of 50 and a standard deviation of 10, with higher scores indicating a greater level of sleep disturbance.
Time frame: up to 180 days after hospital discharge
Co-administration of Analgesics
Total opioid dose in fentanyl equivalents
Time frame: 14 days after randomization
Hypotension
Refractory systolic blood pressure \< 90 mm Hg or Mean arterial blood pressure \< 65 mm Hg despite ongoing ICU therapies
Time frame: 14 days after randomization, while on study drug
Bradycardia
Heart rate \< 60 beats per minute despite ongoing ICU therapies
Time frame: 14 days after randomization, while on study drug
Mental Status
New, acute neurologic disturbances such as blurred vision, dizziness, weakness, or vertigo
Time frame: 14 days after randomization, while on study drug
| Milestone | Placebo | IV Guanfacine |
|---|---|---|
| Started | 23 | 23 |
| Completed | 19 | 20 |
| Not completed | 4 | 3 |
| Withdrew: Did not receive any study drug and not included in assessments or results | 4 | 3 |
| days | Placebo | IV Guanfacine |
|---|---|---|
| Number of Days Alive Without Delirium or Coma | 7.00 (2.00 to 10.50) | 8.50 (1.75 to 10.00) |
| days | Placebo | IV Guanfacine |
|---|---|---|
| Days Alive and Free of Mechanical Ventilation | 22.12 (4.18 to 26.90) | 19.71 (4.45 to 27.00) |
| days | Placebo | IV Guanfacine |
|---|---|---|
| Days Alive and Free of the Intensive Care Unit | 19.89 (1.25 to 23.99) | 10.93 (0.00 to 23.01) |
Telephone Montreal Cognitive Assessment has a minimum score of 0 and a maximum score of 22, with higher numbers indicating better cognition. A score of 18 or below is considered a positive screen for at least mild cognitive impairment.
| Units on a scale | Placebo | IV Guanfacine |
|---|---|---|
| Cognitive Function | 19.00 (18.50 to 20.50) | 16.00 (15.00 to 16.50) |
| days | Placebo | IV Guanfacine |
|---|---|---|
| Days Alive and Free of the Hospital | 1.00 (0.00 to 7.93) | 0.00 (0.00 to 1.24) |
| Participants | Placebo | IV Guanfacine |
|---|---|---|
| Mortality | 6 | 10 |
Patient-Reported Outcomes Measurement Information System V.1.2-Physical Function 8b is a process that involves using a specific set of 8 questions to assess a patient's self-reported ability to perform physical activities. These questions are designed to measure a person's physical function, focusing on their ability to perform daily activities, including those involving upper and lower extremities, and central body regions. Patients respond to each question on a scale, typically a five-point scale (e.g., 1 = not at all to 5 = completely). The total raw score is then converted to a T-score using a table provided in the PROMIS scoring manual. T-scores are standardized scores with a mean of 50 and a standard deviation of 10, allowing for comparison across individuals and populations. Higher T-scores generally indicate a higher level of physical function.
| Units on a scale | Placebo | IV Guanfacine |
|---|---|---|
| Physical Function | 31.9 (27.8 to 39.4) | 36.4 (35.9 to 36.9) |
Patient-Reported Outcomes Measurement Information System V.1.1-Global is a 10-item questionnaire that measures physical and mental health in patients. The questionnaire uses a T-score metric, where a score of 50 represents the average for the US population with a standard deviation of 10. Higher T-scores indicate better health.
| T-score | Placebo | IV Guanfacine |
|---|---|---|
| Global Health | 37.4 (30.9 to 42.3) | 36.1 (34.2 to 37.9) |
Patient-Reported Outcomes Measurement Information System V.1.0-Pain Interference 8a measures the self-reported consequences of pain on relevant aspects of a person's life and may include the extent to which pain hinders engagement with social, cognitive, emotional, physical, and recreational activities. It consists of 8 questions, each with a scale ranging from 1 (Not at all) to 5 (Very much). The score is calculated by summing the responses to all 8 questions, resulting in a raw score range from 8 to 40. This raw score is then converted into a T-score, with a mean of 50 and a standard deviation of 10, and a higher T-score indicating more pain interference.
| Units on a scale | Placebo | IV Guanfacine |
|---|---|---|
| Pain Interference | 59.1 (55.2 to 67.5) | 60.5 (57.3 to 63.7) |
Patient-Reported Outcomes Measurement Information System V.1.0-Applied Cognition is designed to assess a patient's self-perceived cognitive abilities and concerns in everyday life. The PROMIS measures use a T-score metric with a mean of 50 and a standard deviation of 10, where higher scores indicate better perceived cognitive functioning.
| Units on a scale | Placebo | IV Guanfacine |
|---|---|---|
| Applied Cognition | 47.7 (42.5 to 53.5) | 49.6 (47.0 to 52.3) |
Patient-Reported Outcomes Measurement Information System V.1.0-Sleep Disturbance utilizes a 5-point Likert scale to assess sleep quality, with higher scores indicating greater sleep disturbance. The scale's T-score is a standardized score with a mean of 50 and a standard deviation of 10, with higher scores indicating a greater level of sleep disturbance.
| Units on a scale | Placebo | IV Guanfacine |
|---|---|---|
| Sleep | 57.0 (48.7 to 64.4) | 52.8 (48.3 to 57.2) |
Total opioid dose in fentanyl equivalents
| mcg | Placebo | IV Guanfacine |
|---|---|---|
| Co-administration of Analgesics | 4369 (1926 to 8229) | 1883 (638 to 4255) |
Refractory systolic blood pressure \< 90 mm Hg or Mean arterial blood pressure \< 65 mm Hg despite ongoing ICU therapies
| Participants | Placebo | IV Guanfacine |
|---|---|---|
| Hypotension | 0 | 0 |
Heart rate \< 60 beats per minute despite ongoing ICU therapies
| Participants | Placebo | IV Guanfacine |
|---|---|---|
| Bradycardia | 0 | 0 |
New, acute neurologic disturbances such as blurred vision, dizziness, weakness, or vertigo
| Participants | Placebo | IV Guanfacine |
|---|---|---|
| Mental Status | 0 | 0 |
Collected over 180 days from randomization. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | 6/19 (31.6%) | 0/19 (0%) | 0/19 (0%) |
| IV Guanfacine | 10/20 (50%) | 0/20 (0%) | 1/20 (5%) |
| Event | Placebo | IV Guanfacine |
|---|---|---|
| FallInjury, poisoning and procedural complications | 0/19 | 1/20 |
| Age, Continuous(years) | Placebo | IV Guanfacine | Total |
|---|---|---|---|
| Median | 65.5 (55.9 to 71.4) | 60.5 (52.5 to 69.6) | 62.3 (54.2 to 71.4) |
| Sex: Female, Male(Participants) | Placebo | IV Guanfacine | Total |
|---|---|---|---|
| Female | 9 | 9 | 18 |
| Male | 10 | 11 | 21 |
| Race (NIH/OMB)(Participants) | Placebo | IV Guanfacine | Total |
|---|---|---|---|
| American Indian or Alaska Native | 1 | 0 | 1 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 4 | 0 | 4 |
| White | 14 | 20 | 34 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Ethnicity (NIH/OMB)(Participants) | Placebo | IV Guanfacine | Total |
|---|---|---|---|
| Hispanic or Latino | 0 | 1 | 1 |
| Not Hispanic or Latino | 19 | 19 | 38 |
| Unknown or Not Reported | 0 | 0 | 0 |
| SOFA score at ICU admission(SOFA score) | Placebo | IV Guanfacine | Total |
|---|---|---|---|
| Median | 10 (7 to 14) | 13.5 (10.75 to 15) | 13 (7.5 to 14.5) |
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Vanderbilt University Medical Center