Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| 3R01AG053582-05S1 | U.S. NIH Grant/Contract | View source |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| Massachusetts General Hospital | OTHER |
| National Institute on Aging (NIA) | NIH |
Not provided
Not provided
Not provided
Not provided
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.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | Participants will flow through the trial in the following manner:
|
|
| IV Guanfacine | Experimental | Participants will flow through the trial in the following manner:
|
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Guanfacine | Drug | Patients randomized to the IV Guanfacine arm will receive intravenous guanfacine when they exhibit ICU delirium. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Days Alive Without Delirium or Coma | 14 days after randomization |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Christopher Hughes, MD | Vanderbilt University Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vanderbilt University Medical Center | Nashville | Tennessee | 37212 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37029295 | Derived | Arnsten AFT, Ishizawa Y, Xie Z. Scientific rationale for the use of alpha2A-adrenoceptor agonists in treating neuroinflammatory cognitive disorders. Mol Psychiatry. 2023 Nov;28(11):4540-4552. doi: 10.1038/s41380-023-02057-4. Epub 2023 Apr 7. |
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Participants will flow through the trial in the following manner:
|
| FG001 | IV Guanfacine | Participants will flow through the trial in the following manner:
|
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Participants will flow through the trial in the following manner:
|
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Days Alive Without Delirium or Coma | Posted | Median | Inter-Quartile Range | days | 14 days after randomization |
|
180 days from randomization
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Participants will flow through the trial in the following manner:
Placebo: Patients randomized to the placebo arm will receive intravenous normal saline when they exhibit ICU delirium. |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fall | Injury, poisoning and procedural complications | Non-systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Christopher Hughes | Vanderbilt University Medical Center | 615-322-5000 | christopher.hughes@vumc.org |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 7, 2024 | Apr 10, 2025 | Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Aug 30, 2023 | Feb 4, 2026 | ICF_002.pdf |
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D016638 | Critical Illness |
| D003693 | Delirium |
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D003221 | Confusion |
Not provided
Not provided
| ID | Term |
|---|---|
| D016316 | Guanfacine |
| ID | Term |
|---|---|
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| D010648 | Phenylacetates |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Placebo | Drug | Patients randomized to the placebo arm will receive intravenous normal saline when they exhibit ICU delirium. |
|
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. |
| 180 days after randomization |
| Days Alive and Free of the Hospital | 28 days after randomization |
| Mortality | 90 days after randomization |
| 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. | 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. | 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. | 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. | up to 180 days after hospital discharge |
| Co-administration of Analgesics | Total opioid dose in fentanyl equivalents | 14 days after randomization |
| Hypotension | Refractory systolic blood pressure < 90 mm Hg or Mean arterial blood pressure < 65 mm Hg despite ongoing ICU therapies | 14 days after randomization, while on study drug |
| Bradycardia | Heart rate < 60 beats per minute despite ongoing ICU therapies | 14 days after randomization, while on study drug |
| Mental Status | New, acute neurologic disturbances such as blurred vision, dizziness, weakness, or vertigo | 14 days after randomization, while on study drug |
| BG001 | IV Guanfacine | Participants will flow through the trial in the following manner:
|
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| SOFA score at ICU admission | Severity of illness at ICU admission as measured by the Sequential Organ Failure Assessment (SOFA) score. This is used to assess the severity of organ dysfunction in critically ill patients, with each organ system (respiratory, cardiovascular, hepatic, coagulation, renal, and central nervous system) receiving a score from 0 (normal) to 4 (most abnormal), resulting in a total score ranging from 0 (normal) to 24 (most abnormal, severe). | Median | Inter-Quartile Range | SOFA score |
|
Participants will flow through the trial in the following manner:
|
|
| Secondary | Days Alive and Free of Mechanical Ventilation | Posted | Median | Inter-Quartile Range | days | 28 days after randomization |
|
|
|
| Secondary | Days Alive and Free of the Intensive Care Unit | Posted | Median | Inter-Quartile Range | days | 28 days after randomization |
|
|
|
| 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. | Posted | Median | Inter-Quartile Range | Units on a scale | 180 days after randomization |
|
|
|
| Secondary | Days Alive and Free of the Hospital | Posted | Median | Inter-Quartile Range | days | 28 days after randomization |
|
|
|
| Secondary | Mortality | Posted | Count of Participants | Participants | 90 days after randomization |
|
|
|
| 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. | Posted | Median | Inter-Quartile Range | Units on a scale | 180 days after after randomization |
|
|
|
| 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. | Posted | Median | Inter-Quartile Range | T-score | 180 days after after randomization |
|
|
|
| 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. | Posted | Median | Inter-Quartile Range | Units on a scale | 180 days after randomization |
|
|
|
| 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. | Posted | Median | Inter-Quartile Range | Units on a scale | 180 days after randomization |
|
|
|
| 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. | Posted | Median | Inter-Quartile Range | Units on a scale | up to 180 days after hospital discharge |
|
|
|
| Other Pre-specified | Co-administration of Analgesics | Total opioid dose in fentanyl equivalents | Posted | Median | Inter-Quartile Range | mcg | 14 days after randomization |
|
|
|
| Other Pre-specified | Hypotension | Refractory systolic blood pressure < 90 mm Hg or Mean arterial blood pressure < 65 mm Hg despite ongoing ICU therapies | Posted | Count of Participants | Participants | 14 days after randomization, while on study drug |
|
|
|
| Other Pre-specified | Bradycardia | Heart rate < 60 beats per minute despite ongoing ICU therapies | Posted | Count of Participants | Participants | 14 days after randomization, while on study drug |
|
|
|
| Other Pre-specified | Mental Status | New, acute neurologic disturbances such as blurred vision, dizziness, weakness, or vertigo | Posted | Count of Participants | Participants | 14 days after randomization, while on study drug |
|
|
|
| 6 |
| 19 |
| 0 |
| 19 |
| 0 |
| 19 |
| EG001 | IV Guanfacine | Participants will flow through the trial in the following manner:
Guanfacine: Patients randomized to the IV Guanfacine arm will receive intravenous guanfacine when they exhibit ICU delirium. | 10 | 20 | 0 | 20 | 1 | 20 |
Not provided
Not provided
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D003072 | Cognition Disorders |
| D000146 |
| Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| Unknown or Not Reported |
|