Exogenous Ketone Supplementation in ICU Delirium

NCT07364162 | Not Yet Recruiting Phase 1 FDA Drug

• 1 other identifier: U16370
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Delirium is a common syndrome in intensive care unit (ICU) patients. Those experiencing delirium may suddenly feel confused, have trouble thinking clearly, struggle to pay attention, or see and hear things that are not real. Delirium is associated with worse long-term outcomes such as cognitive impairment, depression, and PTSD (post-traumatic stress disorder). This study examines whether an investigational medical-grade ketone supplement drink (ketone monoester \[brand name: Ultrapure Ketone Monoester\]) is safe and feasible to use in ICU patients, and to look for signals that it might reduce delirium or shorten its duration compared to a volume-, taste-, and calorie-matched placebo.

Conditions

ICU Delirium; Critical Illness

Keywords

ICU; Intensive Care Unit; Critical care; Critical illness; Ketones

Outcome Measures

Primary Outcomes (2)

• Feasibility: Proportion of participants achieving target peak serum β-hydroxybutyrate (1.5-3.5 mmol/L) on at least 50% of dosing days

  Peak serum β-hydroxybutyrate will be measured once daily using safety laboratories drawn 60-90 minutes after the morning ketone dose to capture the post-dose peak level. A dosing day will be considered successful if the measured peak serum β-hydroxybutyrate is within 1.5-3.5 mmol/L. The primary feasibility outcome is the proportion of participants in the ketone group who have successful peak serum β-hydroxybutyrate measurements on ≥50% of dosing days during the dosing period. Feasibility will be considered met if ≥70% of participants in the ketone group meet this criterion.

  From enrollment through study day 7 or ICU discharge.

• Safety and tolerability: Number of participants with ≥1 prespecified safety or tolerability event

  A prespecified safety or tolerability event is defined as any of the following occurring from enrollment through study day 7: acid-base abnormality (blood gas pH \<7.20 or serum bicarbonate \<8 mmol/L), off-target hyperketonemia (peak serum β-hydroxybutyrate \>3.5 mmol/L despite dose reduction), hypoglycemia (\<60 mg/dL), renal or hepatic safety signal (new dialysis initiation; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>5× upper limit of normal, or total bilirubin \>3 mg/dL without alternative explanation), hemodynamic instability temporally related to dosing, or gastrointestinal symptoms (nausea, vomiting, diarrhea, cramping) recorded as tolerability adverse events. The outcome will be summarized as the number of participants with ≥1 prespecified event by treatment arm.

  From enrollment through study day 7.

Secondary Outcomes (17)

• Feasibility: Proportion of scheduled post-dose serum β-hydroxybutyrate draws completed

  From enrollment through study day 7 or ICU discharge.

• Feasibility: Proportion of post-dose serum β-hydroxybutyrate measurements >4.0 mmol/L

  From enrollment through study day 7 or ICU discharge.

• Feasibility: Adherence to ketone dose-titration algorithm

  From enrollment through study day 7 or ICU discharge.

• Delirium- and coma-free days (DCFDs) through study day 7

  From enrollment through study day 7.

• Delirium severity score on the Confusion Assessment Method for the Intensive Care Unit-7 (CAM-ICU-7) scale

  From enrollment through study day 7.

Study Arms (2)

Ketone monoester

EXPERIMENTAL

Drug: Ketone monoester

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Placebo DRUG

Placebo consists of 74 mL of dextrose 50% in water (D50W) plus 50 mg sucrose octaacetate for taste matching; administered enterally (oral/feeding tube) on the same schedule as the experimental arm.

Placebo

Ketone monoester DRUG

Ketone monoester diluted to a total volume of 74 mL with water and administered enterally (oral/feeding tube). Dosing is protocolized with an initial dose of 25 g and subsequent dose titration based on serum β-hydroxybutyrate levels to target a prespecified serum β-hydroxybutyrate range, administered every 6 hours for up to 7 days (or ICU discharge or death, whichever occurs first).

Also known as: (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, D-β-hydroxybutyrate monoester, D-BHB monoester, (R)-hydroxybutyl (R)-3-hydroxybutyrate;, [(3R)-3-hydroxybutyl] (3R)-3-hydroxybutanoate)

Ketone monoester

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients (≥18 years old) admitted to the medical intensive care unit.
• Current ICU admission with anticipated ICU stay ≥24 hours.
• Enteral access in place, planned enteral access placement, or PO intake appropriate, and the ability to receive enteral dosing within 24 hours of enrollment.
• Ability to complete delirium assessments (CAM-ICU feasible) at time of enrollment.

You may not qualify if:

• Severe metabolic acidosis at screening: blood gas pH \<7.20 or bicarbonate \< 8 mmol/L.
• Diabetic ketoacidosis as an ICU admission diagnosis or hyperketonemia from any ketoacidosis state.
• Hypoglycemia as an ICU admission diagnosis or glucose \<60 mg/dL.
• Patients with a history of type 1 diabetes mellitus.
• Hemoglobin \<7.0.
• Fulminant hepatic failure or AST/ALT \> 5× ULN or total bilirubin \> 3 mg/dL.
• Refractory shock (defined as norepinephrine dose ≥20 µg/min or use of a second vasopressor agent).
• Pregnancy (positive urine/serum hCG at screening or known pregnancy).
• Uncontrolled ileus or gastrointestinal condition, such as an upper gastrointestinal bleed, preventing enteral dosing.
• SGLT2 inhibitor use within the prior 7 days.
• ADH/ALDH inhibitors (e.g., fomepizole, disulfiram) use in the prior 7 days or planned.
• Benzodiazepine dependency or alcohol dependency based on the medical team's decision to institute a specific treatment plan involving benzodiazepines or barbiturates (either as continuous infusions or intermittent intravenous boluses) for this dependency.
• Active seizures during this ICU admission being treated with intravenous benzodiazepines.
• Expected death within 24 hours of enrollment or lack of commitment to aggressive treatment by family/medical team (e.g., likely to withdraw life support measures within 24 hours of screening).
• Admission to ICU only for post-operative monitoring or frequent neurologic assessments.

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

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MeSH Terms

Conditions

Critical Illness; Ketosis

Interventions

(R)-3-hydroxybutyl (R)-3-hydroxybutyrate

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Acidosis; Acid-Base Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• E. Wes Ely, MD, MPH

  Vanderbilt University Medical Center

  STUDY DIRECTOR

• Ryan J Smith, MD, JD

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ryan J Smith, MD, JD

CONTACT

(602) 538-5003; ryan.j.smith@vumc.org

Rebecca Abel, MA

CONTACT

6158753763; wes.ely@vumc.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Pulmonary & Critical Care Medicine Fellow, Vanderbilt University Medical Center

Study Record Dates

• First Submitted: January 9, 2026
• First Posted: January 23, 2026
• Study Start: April 6, 2026
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027
• Last Updated: March 31, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: IPD and supporting documents will be available beginning 9 months after publication of the primary results and will remain available for 36 months following publication.
• Access Criteria: De-identified IPD and supporting documents will be shared with qualified researchers who submit a methodologically sound proposal. Access requires approval by the study team, execution of a data use agreement, and IRB/ethics approval as applicable. Data will be provided via secure electronic transfer. Requestors must agree not to attempt re-identification and to use the data only for the approved purpose.

Locations

US (1)