Clinical trial NCT05085808: RCT: Trazodone vs Quetiapine vs Placebo for Treating ICU Delirium (TraQ)
Official title: Comparison of Trazodone vs Quetiapine vs Placebo for the Treatment of ICU Delirium: A Randomized Controlled Trial (The TraQ Study)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Delirium
Morality
Quality of Life
Psych
Treatment Side Effects
Keywords: delirium
quetiapine
trazodone
critical care
ICU delirium
Lead sponsor: University of Southern California
Sponsor class: OTHER
First posted: 2021-10-20
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of this study is to evaluate the effectiveness of trazodone as compared to quetiapine and placebo, in the management of ICU delirium in adult (\>=18 years old) surgical ICU patients. The investigators will compare outcomes such as delirium incidence and duration, in-hospital mortality, 28-day mortality, hospital length of stay (LOS), ICU LOS, mechanical ventilator days, complications, adverse effects, rescue medication use, delirium symptom severity, sleep duration, and sleep quality among participants receiving trazodone, quetiapine, or placebo. The investigators hypothesize participants receiving trazodone will have a shorter duration of delirium, decreased delirium severity, and improved sleep quality compared to participants receiving quetiapine and placebo.

Detailed description: This is a single-center, double-blind randomized, placebo-controlled pilot trial comparing trazodone, quetiapine, and placebo for the treatment of ICU delirium in adult patients admitted to the surgical ICU at Keck Hospital of the University of Southern California.

The purpose of this study is to determine the effectiveness of several medications (trazodone, quetiapine and placebo) used for the treatment of ICU delirium, and their effects on patient outcomes. Since the incidence of ICU delirium is high and has profound negative ramifications on survival, long-term outcomes, cognitive function, in addition to placing a heavy burden on the healthcare system resources and costs, effective delirium treatment strategies are desperately needed. Trazodone is a medication that has promise in delirium treatment, but there is currently insufficient literature to recommend its routine use. The investigators' main objective is to determine if trazodone is an effective and safe treatment option for the management of ICU delirium, and if it results in shorter delirium duration and improved outcomes compared to participants receiving quetiapine and placebo.

Subject screening:

All patients will be screened for study eligibility daily on rounds throughout the study period. Patients eligible for the study will be asked for written informed consent (signed by either the patient or the surrogate decision maker) after admission (even if the patient does not have delirium), or at any point during the ICU course (patient may or may not have a delirium diagnosis at the time of consent).

ICU nurses will assess all patients for delirium at least every 12 hours, using the CAM-ICU tool , in accordance with the standard of care in the surgical ICU (that is, this assessment would be performed regardless of the study).

Patients who have written informed consent, have a diagnosis of delirium (CAM-ICU positive) that requires pharmacological intervention as determined by the attending intensivist, and meet all inclusion criteria and have no exclusion criteria, will be randomized to receive either trazodone, quetiapine, or placebo.

Stratification/Randomization Scheme: Patients who are enrolled in the study, meet randomization inclusion criteria, and have no exclusion criteria, and require a medication intervention for the treatment of ICU delirium, as determined by the attending ICU physician, will be randomized to one of three study arms: 1. Trazodone; 2. Quetiapine or; 3. placebo.

Enrolled patients will be randomized in a 1:1:1 ratio to the Trazodone, Quetiapine, or placebo groups. Randomization will be stratified on age (\< vs. ≥65) and delirium severity and occur in blocks, with block size not revealed to investigators. An independent statistician from the USC Clinical and Translational Science Institute (CTSI), will generate a randomization list and import it to REDCap prior to study initiation. Upon confirmation of informed consent, trial eligibility and completion of the baseline assessment, the patient will be randomized to one of the study arms using the REDCap randomization module.

Upon randomization, an automated email notification will be sent to the un-blinded pharmacist (who is not part of the study team), who securely accesses the randomization module on REDCap and will prepare numbered supplement bottles according to the randomization list. The pharmacist will assign and dispense the drug to the ICU nurse who is administering the drug (and is blinded to the medication). The rest of the study team (PIs, co-PIs, research assistants, ICU nurses) will be blinded to the therapy being received and they will be blinded to the randomization and allocation process on REDCap as well, as the allocation and randomization files will be blinded and securely kept under passcode protection by the independent pharmacist. The patients will not know which study medication they are receiving. USC Plaza Pharmacy will prepare the study medications and packaging prior to study initiation.

Study Medication Administration:

There will be standardized method delineating how to begin dosing the study medication, and how to adjust the dose and frequency as needed. Additionally, there will be standardized tapering protocol, so there is consistency among all participants. Furthermore, there will be a standardized rescue medication protocol in place, should patients who are receiving placebo, or having break through delirium despite intervention.

Statistics/Analysis Plan:

-Determination of sample size: As this is a pilot study, a total sample size of 30 (10 per treatment group) over an enrollment period of 1 year is estimated to be recruited based on feasibility. As the primary goal of this pilot study is to identify a signal for treatment efficacy, sample size considerations are based on the precision (i.e., 95% confidence interval) with which key trial parameters can be estimated.

-Baseline descriptive statistics: Baseline characteristics of the study population will be presented by treatment group using conventional descriptive statistics methods, including proportions for categorical variables and means and standard deviations or medians and interquartile ranges for continuous variables, as appropriate based on the data distribution. Comparisons of baseline variables will be performed between treatment groups by one-way Analysis of Variance (ANOVA) for continuous variables and chi-square or Fisher's exact tests for categorical variables, as appropriate. If a statistically significant difference is found (p\<0.05) in the ANOVA models, pairwise treatment comparisons will be performed using Tukey's multiple comparison adjustment. Assumptions of the ANOVA model will be tested including 1) normality of model residuals, 2) homogeneity of variance, and 3) independence of observations and if not met, the non-parametric equivalent Kruskal-Wallis test will be used.

-Analysis of primary endpoints: The primary outcome is the duration of ICU delirium measured in days. Differences in the duration of delirium between treatment groups will be analyzed by Poisson regression or negative binomial regression if there is evidence of over-dispersion. Patients with delirium episodes lasting less than one day will be classified as zero days. All models will include the randomized group and randomization stratification variables as independent variables. Model coefficients for each treatment group will be exponentiated to give the estimated rate ratio of each treatment comparison, with 95% confidence intervals. The referent group for treatment group comparisons will be the placebo group (i.e., comparing trazodone to placebo, and quetiapine to placebo). The pairwise comparison of trazodone to quetiapine will also be conducted.

-Analysis of secondary endpoints: Binary secondary endpoints include the proportion of patients with in-hospital mortality, 28-day mortality, who experience complications, and who use rescue medications. The proportion in each treatment group will be compared univariately by the chi-square or Fisher's exact test and in a multivariable model by binary logistic regression.

Additional secondary endpoints include the length of hospital stay, length of ICU stay, and duration of mechanical ventilation (if applicable). These outcomes will be analyzed as described in the "analysis of primary endpoint".

Trial outcomes that are measured daily (delirium severity measured by CAM-S, nightly sleep duration (hours), number of times awoken at night, and sleep quality (Richards Campbell Sleep Questionnaire) will be compared among treatment groups using generalized linear mixed effects models (GLMMs). Normally distributed continuous outcomes will use a normal random outcome with an identify link function; count outcomes (e.g., number of times awoken) will use a Poisson random variable with a log link function. For each model, the primary independent variables will be randomized treatment group and randomization stratification variables. Assessment time (day of assessment, from day 0 to 14) will be treated as indicator variables. The main effect of treatment will estimate the mean of the outcome among treatment groups over the treatment period. An interaction term of treatment-by-day will be used to estimate treatment group means (with SEs and confidence intervals) by intervention day.

-Analysis of safety measures: Numbers and percentages of adverse events and serious adverse events will be cross-tabulated and summarized descriptively by treatment group. No formal statistical analysis will be conducted.

-Populations for analysis: The full analysis dataset will be based on an intention-to-treat (ITT) principle and will be comprised of all study participants who have been randomized to any of the 3 treatment groups. Analysis will be based on the original intervention, regardless of actual intervention received.

Eligibility criteria: Inclusion Criteria:

1. \>=18-years-old
2. Admitted to the surgical ICU for \>24 hours
3. Written informed consent obtained from the patient or their surrogate decision maker.
4. Diagnosis of ICU delirium defined by positive CAM-ICU score AND exhibiting symptomatic delirium (i.e., combative, pulling at lines, a danger to self or others, inability to sleep, hallucinations, etc.), thus, requiring the need for pharmacologic intervention as determined by the attending intensivist

Exclusion Criteria:

1. Acute alcohol or substance abuse withdrawal symptoms/syndrome (i.e., delirium tremens) requiring treatment/intervention (i.e., implementation of the Clinical Institute Withdrawal Assessment for Alcohol (CIWA) protocol, benzodiazepines, alpha-2 agonist, etc.)
2. Recent torsade de pointes or ventricular arrhythmia
3. Prolonged QTc syndrome AND/OR prolonged QT-interval (QTc\>500 ms on baseline EKG, performed on the day of randomization)
4. Active psychosis
5. Patients taking medications with known interactions with either trazodone and/or quetiapine
6. Acute encephalopathy (i.e., hepatic, uremic, etc.)
7. Seizure disorder
8. myocardial infarction (MI) within the past 30 days
9. Tardive dyskinesia
10. Hyponatremia
11. Terminal state
12. Diagnosis of liver disease
13. Patients who are strict NPO, are a high aspiration risk (defined as frequent nausea/vomiting, ileus, gastric dysmotility disorder, uncontrolled GERD, weakness/deconditioning, diabetes with gastroparesis, not tolerating full tube feeds if being enterally fed (high residual gastric volume \>500 cc), elderly patients with waxing/waning mental status), have dysphagia, and/or have difficulty swallowing capsules as determined by speech therapist
14. Patients who have enteral access such as a small-bore feeding tube, nasogastric or orogastric tube, or gastrostomy/gastrojejunostomy tube (as these patients will need medications crushed in order to administer via the tube, and the capsules used in this study cannot be crushed)
15. Presence of an acute neurologic condition (i.e., acute cerebrovascular accident, intracranial tumor, traumatic brain injury, etc.) on ICU admission. History of stroke or other neurological condition(s) without cognitive impairment is not an exclusion criterion.
16. Pregnancy/lactation
17. History of ventricular arrhythmia including torsade de pointes
18. Allergy/hypersensitivity reaction to trazodone and/or quetiapine
19. Diagnosis of dementia
20. History of neuroleptic malignant syndrome and/or serotonin syndrome
21. Diagnosis of Parkinson's disease or parkinsonism (also referred to as hypokinetic rigidity syndrome)
22. Schizophrenia or other psychotic disorder
23. Patients in whom CAM-ICU cannot be performed to screen for delirium (i.e., acute encephalopathy, mental retardation, vegetative state/coma, deaf, blind, etc.)
24. Inability to speak or understand English
25. Expected to die or transfer out of the ICU within 24 hours
26. Currently enrolled and participating in another interventional study
27. No signed written informed consent by patient or their surrogate decision maker.

Primary outcomes:
measure: Delirium duration using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) tool
timeFrame: 14 days
Secondary outcomes:
measure: ICU length of stay
timeFrame: 14 days
measure: hospital length of stay
timeFrame: 14 days
measure: mechanical ventilator duration
timeFrame: 14 days
measure: in-hospital mortality
timeFrame: 14 days
measure: 28-day mortality
timeFrame: 28 days
measure: complications
timeFrame: 14 days
measure: adverse study drug-related reactions
timeFrame: 14 days
measure: Use of rescue medications
timeFrame: 14 days
measure: Delirium severity
timeFrame: 14 days
measure: sleep quality
timeFrame: 14 days
measure: discharge disposition
timeFrame: 14 days
measure: Long-term cognitive function
timeFrame: up to 6 months post-randomization (measured at 1-, 3-, 6-months post-randomization)
measure: Long-term depression
timeFrame: up to 6 months post-randomization (measured at 1-, 3-, 6-months post-randomization)
measure: Long-term anixety
timeFrame: up to 6 months post-randomization (measured at 1-, 3-, 6-months post-randomization)
measure: Long-term PTSD
timeFrame: up to 6 months post-randomization (measured at 1-, 3-, 6-months post-randomization)
measure: Long-term quality of life
timeFrame: up to 6 months post-randomization (measured at 1-, 3-, 6-months post-randomization)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Keck Hospital of the University of Southern California
state: California
Study officials:
affiliation: University of Southern California
name: Catherine M Kuza, MD, FASA
role: PRINCIPAL_INVESTIGATOR
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