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Efficacy and Safety of Risperidone and Trazodone Monotherapy and Combination Therapy in Critically Ill Patients With Delirium

Primary Purpose

Delirium, Agitation

Status

Withdrawn

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Risperidone

Trazodone

Placebo

About this trial

This is an interventional treatment trial for Delirium

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age greater than 18 years old who are admitted for more than 24 hours in the MICU or SICU
Patients diagnosed with delirium by primary team (screened positive for delirium using the CAM-ICU or with clinical manifestations of delirium)
Patients have an order for as-needed haloperidol or have received a one-time dose of haloperidol within 24 hours of randomization
Patients must be tolerating enteral feeding (greater than 20 mL/hour for more than 12 hours)

Exclusion Criteria:

Patients who are unlikely to survive 24 hours after admission to the ICU
Patients who are admitted with a primary neurological condition or injury (i.e. stroke, active seizures, prolonged coma, overdose)
Patients who can not actively participate in delirium assessment
Patients actively withdrawing from alcohol or narcotics
Patients who were treated with any antipsychotic or trazodone within 30 days prior to ICU admission
Patients with a marked baseline prolongation of the QTc interval (repeated demonstration of QTc interval greater 500 milliseconds (msec))
Patients with a history of Torsades de Pointes
Patients with current treatment with an agent having either the potential to affect or increase the risk of QTc prolongation (e.g. erythromycin, any class Ia, Ic, or III antiarrhythmics)
Patients being treated with a neuromuscular blocker
Patients in whom haloperidol, risperidone, or trazodone is contraindicated
Pregnant patients or patients who are breast-feeding
Patients with a modified Blessed dementia rating scale score ≥4 or an Informant Questionnaire of Cognitive Dysfunction in the Elderly Score ≥4
Patients in which informed consent can not be obtained from the legally authorized representative

Sites / Locations

Rochester General Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Placebo

Risperidone alone

Trazodone alone

Risperidone and Trazodone combination

Arm Description

Drug: Placebo Placebo suspension administered PO/NG/FT q12h to mimic risperidone Placebo suspension administered PO/NG/FT q8h to mimic trazodone

Drug: Trazodone Initiate trazodone dosing at 50 mg PO/NG/FT q8h Trazodone dose can be titrated upwards every 24 hours by 25 mg per dose Maximum trazodone daily dose 600 mg per day (200 mg every 8 hours)

Drug: Risperidone Initiate risperidone at 1 mg PO/NG/FT q12h Risperidone dose can be titrated upwards every 24 hours by increments of 0.5 mg per dose Maximum risperidone daily dose of 6 mg per day (3 mg every 12 hours) Drug: Trazodone Initiate risperidone at 1 mg PO/NG/FT q12h Risperidone dose can be titrated upwards every 24 hours by increments of 0.5 mg per dose Maximum risperidone daily dose of 6 mg per day (3 mg every 12 hours)

Outcomes

Primary Outcome Measures

The number of days patients are without delirium during the study period (delirium-free days)

Secondary Outcome Measures

Daily prevalence of delirium as indicated by a positive Confusion Assessment Method in the ICU (CAM-ICU)

Resolution of delirium as indicated by a negative Confusion Assessment Method in the ICU (CAM-ICU) for more than 24 hours

The number of patients who require rescue medications, the type of rescue medications utilized, and the amount of rescue medications per day

The number of patients who receive sedative agents, amount of midazolam equivalents per day, and the number of days in which patients receive a sedative agent

The number of patients who receive pain medications, amount of fentanyl equivalents per day, and the number of days in which patients receive a pain medication

The number of hours spent agitated (RASS score between +4 and +2) as a percent of the time that the study drug was administered

The number of hours spent excessively sedated or in a coma state (RASS score between -4 to -5) as a percent of the time that the study drug was administered

The duration of mechanical ventilation from initial intubation to extubation as long as the patient remained extubated for more than 48 hours.

The number of days that the patients were alive and breathing without assistance during the study period (ventilator-free days)

The number of episodes and number of patients who experience clinically significant QTc prolongation (≥ 500 msec or an increase of more than 60 msec from baseline)

The number of episodes and number of patients who experience clinically significant extrapyramidal effects (as evidenced by a positive Simpson-Angus Scale Score)

All-cause mortality and 28-day mortality

Full Information

NCT ID

NCT02118688

First Posted

April 9, 2014

Last Updated

September 9, 2019

Sponsor

Rochester General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT02118688

Brief Title

Efficacy and Safety of Risperidone and Trazodone Monotherapy and Combination Therapy in Critically Ill Patients With Delirium

Official Title

Efficacy and Safety of Risperidone and Trazodone Monotherapy and Combination Therapy in Critically Ill Patients With Delirium: A Four-arm Prospective, Randomized, Double-blind, Placebo-controlled Pilot Study

Study Type

Interventional

2. Study Status

Record Verification Date

September 2019

Overall Recruitment Status

Withdrawn

Why Stopped

Lack of enrollment

Study Start Date

March 2011 (undefined)

Primary Completion Date

March 2016 (Actual)

Study Completion Date

March 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Rochester General Hospital

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this randomized clinical trial is to determine whether risperidone alone, trazodone alone, or a combination of risperidone and trazodone is superior for the treatment of ICU acquired delirium. The hypothesis is that combination therapy is superior to either agent alone in treating ICU acquired delirium and sustaining delirium free time.

Detailed Description

Delirium is defined as a disturbance of consciousness characterized by an acute onset of impaired cognitive function. Although delirium is thought to be common in the Intensive Care Unit (ICU) there are few studies that have evaluated its incidences, risks and outcomes. It has been associated with increased morbidity, and mortality and increased cost to the healthcare system. In addition to the uncertainty of the incidence of ICU delirium, there is a lack of information about the effects that certain pharmacological treatments have on delirious patients. The rationale for this study is to evaluate the efficacy and safety of risperidone alone, trazodone alone, and risperidone plus trazodone for the treatment of delirium in critically ill patients when compared to placebo.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Delirium, Agitation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Factorial Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Drug: Placebo Placebo suspension administered PO/NG/FT q12h to mimic risperidone Placebo suspension administered PO/NG/FT q8h to mimic trazodone

Arm Title

Risperidone alone

Arm Type

Active Comparator

Arm Description

Arm Title

Trazodone alone

Arm Type

Active Comparator

Arm Description

Arm Title

Risperidone and Trazodone combination

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Risperidone

Intervention Type

Drug

Intervention Name(s)

Trazodone

Intervention Type

Drug

Intervention Name(s)

Placebo

Primary Outcome Measure Information:

Title

The number of days patients are without delirium during the study period (delirium-free days)

Description

The number of days patients are without delirium during the study period (delirium-free days)

Time Frame

Every 24 hours (up to 14 days)

Secondary Outcome Measure Information:

Title

Daily prevalence of delirium as indicated by a positive Confusion Assessment Method in the ICU (CAM-ICU)

Time Frame

Every 24 hours (up to 14 days)

Title

Resolution of delirium as indicated by a negative Confusion Assessment Method in the ICU (CAM-ICU) for more than 24 hours

Time Frame

Every 24 hours (up to 14 days)

Title

The number of patients who require rescue medications, the type of rescue medications utilized, and the amount of rescue medications per day

Time Frame

Every 24 hours (up to 14 days)

Title

The number of patients who receive sedative agents, amount of midazolam equivalents per day, and the number of days in which patients receive a sedative agent

Time Frame

Every 24 hours (up to 14 days)

Title

The number of patients who receive pain medications, amount of fentanyl equivalents per day, and the number of days in which patients receive a pain medication

Time Frame

Every 24 hours (up to 24 hours)

Title

The number of hours spent agitated (RASS score between +4 and +2) as a percent of the time that the study drug was administered

Time Frame

Every 24 hours (up to 14 days)

Title

The number of hours spent excessively sedated or in a coma state (RASS score between -4 to -5) as a percent of the time that the study drug was administered

Time Frame

Every 24 hours (up to 14 days)

Title

The duration of mechanical ventilation from initial intubation to extubation as long as the patient remained extubated for more than 48 hours.

Time Frame

Time (hours) from initial intubation to extubation (as long as patient not reintubated within 48 hours)

Title

The number of days that the patients were alive and breathing without assistance during the study period (ventilator-free days)

Time Frame

Time (days) from extubation to patient discharge (as long as patient not reintubated within 48 hours)

Title

The number of episodes and number of patients who experience clinically significant QTc prolongation (≥ 500 msec or an increase of more than 60 msec from baseline)

Time Frame

QTc interval evaluated q12h during period of study drug administration (up to 14 days)

Title

The number of episodes and number of patients who experience clinically significant extrapyramidal effects (as evidenced by a positive Simpson-Angus Scale Score)

Time Frame

Extrapyramidal effects evaluated by bedside nurse q12h during period of study drug administration (up to 14 days). Investigator will confirm RN suspicion of extrapyramidal effects using Simpson-Angus Score.

Title

All-cause mortality and 28-day mortality

Time Frame

At 14 and 28 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age greater than 18 years old who are admitted for more than 24 hours in the MICU or SICU Patients diagnosed with delirium by primary team (screened positive for delirium using the CAM-ICU or with clinical manifestations of delirium) Patients have an order for as-needed haloperidol or have received a one-time dose of haloperidol within 24 hours of randomization Patients must be tolerating enteral feeding (greater than 20 mL/hour for more than 12 hours) Exclusion Criteria: Patients who are unlikely to survive 24 hours after admission to the ICU Patients who are admitted with a primary neurological condition or injury (i.e. stroke, active seizures, prolonged coma, overdose) Patients who can not actively participate in delirium assessment Patients actively withdrawing from alcohol or narcotics Patients who were treated with any antipsychotic or trazodone within 30 days prior to ICU admission Patients with a marked baseline prolongation of the QTc interval (repeated demonstration of QTc interval greater 500 milliseconds (msec)) Patients with a history of Torsades de Pointes Patients with current treatment with an agent having either the potential to affect or increase the risk of QTc prolongation (e.g. erythromycin, any class Ia, Ic, or III antiarrhythmics) Patients being treated with a neuromuscular blocker Patients in whom haloperidol, risperidone, or trazodone is contraindicated Pregnant patients or patients who are breast-feeding Patients with a modified Blessed dementia rating scale score ≥4 or an Informant Questionnaire of Cognitive Dysfunction in the Elderly Score ≥4 Patients in which informed consent can not be obtained from the legally authorized representative

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mindee S Hite, Pharm.D.

Organizational Affiliation

Rochester General Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Rochester General Hospital

City

Rochester

State/Province

New York

ZIP/Postal Code

14621

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Efficacy and Safety of Risperidone and Trazodone Monotherapy and Combination Therapy in Critically Ill Patients With Delirium

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