Critical IllnessPhase 2MENDINGNCT04742673
Maximizing trEatment of Neurological Dysfunction Using INtravenous Guanfacine Study
A Phase 2 study testing Guanfacine in people with Critical Illness and Delirium, run by Vanderbilt University Medical Center at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Critical Illness, Delirium, Cognitive Impairment
- What is being tested?
- Guanfacine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 46 participants
- Where
- 1 siteUnited States
- Study dates
- 4 May 2021to 30 Nov 2025
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- adult patients (≥ 18 years old)
- requiring admission to an ICU
- 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]).
Who cannot join
- allergic to guanfacine, clonidine, or dexmedetomidine
- on home antipsychotics who, therefore, require continuing antipsychotic administration in the hospital
- 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.
- co-enrolled in another interventional trial examining similar outcomes or in a study that does not allow co-enrollment
- 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)
- 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).
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- dementia or other chronic neurologic disease or disorder that makes the patient incapable of living independently at baseline
- active substance abuse, psychotic disorder, or homelessness without a secondary contact person (which would make long-term follow-up difficult)
- blindness or deafness (which would prevent assessment of the study's outcomes)
- pregnancy or breastfeeding
- prisoner
- inability to start informed consent process within 72 hours from the time that all inclusion criteria were met
- Cardiac surgery within the current hospitalization.
Trial locations and contacts
1 site in 1 country.
United States1 site
Vanderbilt University Medical Center
Nashville, Tennessee, 37212
About this study
This proof-of-concept study examines whether the acute brain dysfunction that occurs in critically ill patients is improved by administration of intravenous guanfacine.
Read the 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.
- Conditions
- Critical Illness, Delirium, Cognitive Impairment
- Being tested
- Guanfacine, Placebo
- Medical subject headings
- Critical Illness, Delirium, Cognitive Dysfunction
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GuanfacineDrug
Patients randomized to the IV Guanfacine arm will receive intravenous guanfacine when they exhibit ICU delirium.
PlaceboDrug
Patients randomized to the placebo arm will receive intravenous normal saline when they exhibit ICU delirium.
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | 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. Receives: Drug: Placebo |
| IV Guanfacine | Experimental | 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. Receives: Drug: Guanfacine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Days Alive Without Delirium or Coma
Measured: 14 days after randomization
Secondary outcomes (5)
Days Alive and Free of Mechanical Ventilation
Measured: 28 days after randomization
Days Alive and Free of the Intensive Care Unit
Measured: 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.
Measured: 180 days after randomization
Days Alive and Free of the Hospital
Measured: 28 days after randomization
Mortality
Measured: 90 days after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Feb 2021
- Study start4 May 2021
- Primary completion30 Mar 2024
- Study completion30 Nov 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Critical IllnessStudies of the same condition, open and under way.
- More trials run by Vanderbilt University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 46 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Massachusetts General Hospital, National Institute on Aging (NIA)
- Responsible party
- Principal investigator, Christopher G Hughes, Vanderbilt University Medical Center
- Investigators
- Christopher Hughes, MD, Principal investigator, Vanderbilt University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04742673
- Sponsor's protocol ID
- U11543
- Other IDs
- 3R01AG053582-05S1
- Acronym
- MENDING
- Status last verified
- May 2025
- First submitted
- 29 Jan 2021
- Last updated
- 19 Feb 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
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.
PubMed 37029295
Study at a glance
From the registry record, last updated by the sponsor on 19 Feb 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Maximizing trEatment of Neurological Dysfunction Using INtravenous Guanfacine Study
- ClinicalTrials.gov ID
- NCT04742673
- Acronym / sponsor ID
- MENDING / U11543
- Conditions
- Critical Illness, Delirium, Cognitive Impairment
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 46 participants (actual)
- Lead sponsor
- Vanderbilt University Medical CenterUniversity, hospital or other
- Collaborators
- Massachusetts General Hospital, National Institute on Aging (NIA)
- Study start
- 4 May 2021 (actual)
- Primary completion
- 30 Mar 2024 (actual)
- Study completion
- 30 Nov 2025 (actual)
- First posted
- 8 Feb 2021 (actual)
- Results
- Posted 6 May 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: PlaceboParticipants 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. |
| IV Guanfacine | Experimental | Drug: GuanfacineParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- adult patients (≥ 18 years old)
- requiring admission to an ICU
- 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]).
Key exclusion criteria (13 listed)
- allergic to guanfacine, clonidine, or dexmedetomidine
- on home antipsychotics who, therefore, require continuing antipsychotic administration in the hospital
- 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.
- co-enrolled in another interventional trial examining similar outcomes or in a study that does not allow co-enrollment
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GuanfacinePatients randomized to the IV Guanfacine arm will receive intravenous guanfacine when they exhibit ICU delirium. | Drug | IV Guanfacine |
| PlaceboPatients randomized to the placebo arm will receive intravenous normal saline when they exhibit ICU delirium. | Drug | Placebo |
Primary outcome
Number of Days Alive Without Delirium or Coma
Time frame: 14 days after randomization
5 secondary outcomes
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
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Feb 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37029295Arnsten 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Christopher Hughes, MD principal investigator
Vanderbilt University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Guanfacine in people with Critical Illness and Delirium, run by Vanderbilt University Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 6 May 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Days Alive Without Delirium or Coma (time frame: 14 days after randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04742673, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Feb 2026.