Cognitive Impairment, Critical Illness, Delirium
Conditions
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.
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.
Interventions
DRUGGuanfacine
Patients randomized to the IV Guanfacine arm will receive intravenous guanfacine when they exhibit ICU delirium.
DRUGPlacebo
Patients randomized to the placebo arm will receive intravenous normal saline when they exhibit ICU delirium.
Sponsors
Vanderbilt University Medical Center
Massachusetts General Hospital
National Institute on Aging (NIA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Days Alive Without Delirium or Coma | 14 days after randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Days Alive and Free of Mechanical Ventilation | 28 days after randomization | — |
| Days Alive and Free of the Intensive Care Unit | 28 days after randomization | — |
| Cognitive Function | 180 days after randomization | 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. |
| Days Alive and Free of the Hospital | 28 days after randomization | — |
| Mortality | 90 days after randomization | — |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORChristopher Hughes, MD
Vanderbilt University Medical Center
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 19 |
| IV Guanfacine 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. | 20 |
| Total | 39 |
Baseline characteristics
| Characteristic | Total | Placebo | IV Guanfacine |
|---|---|---|---|
| Age, Continuous | 62.3 years | 65.5 years | 60.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 19 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 34 Participants | 14 Participants | 20 Participants |
| Sex: Female, Male Female | 18 Participants | 9 Participants | 9 Participants |
| Sex: Female, Male Male | 21 Participants | 10 Participants | 11 Participants |
| SOFA score at ICU admission | 13 SOFA score | 10 SOFA score | 13.5 SOFA score |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 19 | 10 / 20 |
| other Total, other adverse events | 0 / 19 | 1 / 20 |
| serious Total, serious adverse events | 0 / 19 | 0 / 20 |
Outcome results
Primary
Number of Days Alive Without Delirium or Coma
Time frame: 14 days after randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Number of Days Alive Without Delirium or Coma | 7.00 days |
| IV Guanfacine | Number of Days Alive Without Delirium or Coma | 8.50 days |
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Cognitive Function | 19.00 Units on a scale |
| IV Guanfacine | Cognitive Function | 16.00 Units on a scale |
Secondary
Days Alive and Free of Mechanical Ventilation
Time frame: 28 days after randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Days Alive and Free of Mechanical Ventilation | 22.12 days |
| IV Guanfacine | Days Alive and Free of Mechanical Ventilation | 19.71 days |
Secondary
Days Alive and Free of the Hospital
Time frame: 28 days after randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Days Alive and Free of the Hospital | 1.00 days |
| IV Guanfacine | Days Alive and Free of the Hospital | 0.00 days |
Secondary
Days Alive and Free of the Intensive Care Unit
Time frame: 28 days after randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Days Alive and Free of the Intensive Care Unit | 19.89 days |
| IV Guanfacine | Days Alive and Free of the Intensive Care Unit | 10.93 days |
Secondary
Mortality
Time frame: 90 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Mortality | 6 Participants |
| IV Guanfacine | Mortality | 10 Participants |
Other Pre-specified
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Applied Cognition | 47.7 Units on a scale |
| IV Guanfacine | Applied Cognition | 49.6 Units on a scale |
Other Pre-specified
Bradycardia
Heart rate \< 60 beats per minute despite ongoing ICU therapies
Time frame: 14 days after randomization, while on study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Bradycardia | 0 Participants |
| IV Guanfacine | Bradycardia | 0 Participants |
Other Pre-specified
Co-administration of Analgesics
Total opioid dose in fentanyl equivalents
Time frame: 14 days after randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Co-administration of Analgesics | 4369 mcg |
| IV Guanfacine | Co-administration of Analgesics | 1883 mcg |
Other Pre-specified
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Global Health | 37.4 T-score |
| IV Guanfacine | Global Health | 36.1 T-score |
Other Pre-specified
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Hypotension | 0 Participants |
| IV Guanfacine | Hypotension | 0 Participants |
Other Pre-specified
Mental Status
New, acute neurologic disturbances such as blurred vision, dizziness, weakness, or vertigo
Time frame: 14 days after randomization, while on study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Mental Status | 0 Participants |
| IV Guanfacine | Mental Status | 0 Participants |
Other Pre-specified
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Pain Interference | 59.1 Units on a scale |
| IV Guanfacine | Pain Interference | 60.5 Units on a scale |
Other Pre-specified
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Physical Function | 31.9 Units on a scale |
| IV Guanfacine | Physical Function | 36.4 Units on a scale |
Other Pre-specified
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Sleep | 57.0 Units on a scale |
| IV Guanfacine | Sleep | 52.8 Units on a scale |