Haloperidol Prophylaxis in Older Emergency Department Patients (HARPOON)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by VU University Medical Center
Sponsor:
Information provided by (Responsible Party):
Prabath W.B. Nanayakkara, VU University Medical Center
ClinicalTrials.gov Identifier:
NCT01530308
First received: December 22, 2011
Last updated: June 10, 2014
Last verified: June 2014
  Purpose

The investigators propose a multicenter, randomised, double-blinded, placebo-controlled trial to study the effect of additive low-dose haloperidol prophylaxis on top of exciting care in a general population of older patients (age 70 years and over) acutely admitted to the hospital trough the emergency department (ED) for internal medicine or surgical specialism, and who are at-risk for developing in-hospital delirium on admission according to the VMS delirium risk questions (one or more positive answers out of three questions).

The investigators hypothesize that this intervention will reduce the incidence of in-hospital delirium as well as duration and severity of delirium.


Condition Intervention Phase
Delirium
Drug: Haloperidol
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Early Pharmacological Intervention to Prevent Delirium: Haloperidol Prophylaxis in Older Emergency Department Patients

Resource links provided by NLM:


Further study details as provided by VU University Medical Center:

Primary Outcome Measures:
  • The initial day and number of days there is a significant change from baseline in the mean Delirium Observation Screening (DOS) score, and/or delirium is diagnosed according to the DSM-IV criteria. [ Time Frame: Assessed from 1st day of inclusion, during the 7-day intervention period, up to hospital discharge. ] [ Designated as safety issue: No ]
    Reflecting the incidence, duration and severity of in-hospital delirium, which is the number of days in-hospital delirium is present in each participant who developed documented in-hospital delirium. Delirium symptoms are observed according to a mean Delirium Observation Screening (DOS) score >3 out of three DOS scale scores/24 hours (indicating significant change), and diagnosed according to meeting the DSM-IV delirium criteria.


Secondary Outcome Measures:
  • The number of days before there is a significant change from baseline in the mean Delirium Observation Screening (DOS) score, and delirium is diagnosed according to the DSM-IV delirium criteria. [ Time Frame: Assessed from 1st day of inclusion, during the 7-day intervention period, up to delirium diagnosis or hospital discharge. ] [ Designated as safety issue: No ]
    Reflecting the time-to-develop delirium, which are the number of days from admission day until the first day delirium is diagnosed, assessed up to the day delirium develops during admission or participant is discharged from hospital. Delirium is diagnosed according to a mean Delirium Observation Screening (DOS) score >3 out of three DOS scale scores/24 hours (indicating significant change), and meeting DSM-IV criteria.

  • The (mean) number of days subjects are admitted to the hospital. [ Time Frame: Assessed from 1st day of admission up to hospital discharge. ] [ Designated as safety issue: No ]
    The number of admission days per subject will be used to evaluate the mean hospital length of stay (LOS) in both study arms. The mean LOS is defined by the mean number of days each participant is admitted to hospital, assessed from admission day up to discharge date.

  • Functionality at baseline according to the Index of Independence in Activities of Daily Living (ADL) [ Time Frame: 1 day of hospital admission. ] [ Designated as safety issue: No ]
    Functionality at baseline will be assessed according to the 6-item Index of Independence in Activities of Daily Living (ADL), administered on admission. Scores rang from 0-6 for both women and men, with higher scores indicating high function/independent.

  • Change from baseline functionality at 3 months according to the Index of Independence in Activities of Daily Living (ADL) [ Time Frame: From baseline to assessment at time point 90 days after discharge date. ] [ Designated as safety issue: No ]
    Change from baseline functionality at 3 months after discharge date will be assessed at time point 90 days from hospital discharge date, according to the 6-item Index of Independence in Activities of Daily Living (ADL).

  • Change from baseline functionality at 6 months according to the Index of Independence in Activities of Daily Living (ADL). [ Time Frame: From baseline to assessment at 180 days after discharge date. ] [ Designated as safety issue: No ]
    Change in functionality from baseline at 6 months after discharge date will be assessed at time point 180 days from hospital discharge date, according to the 6-item Index of Independence in Activities of Daily Living (ADL).

  • Functionality at baseline according to the Instrumental Activities of Daily Living Scale (IADL). [ Time Frame: 1 day of hospital admission. ] [ Designated as safety issue: No ]
    Functionality at baseline will be assessed according to the 8-item Instrumental Activities of Daily Living Scale (IADL), administered on admission. Scores range from 0-8 for women, and 0-5 for men with higher scores indicating high function/independent.

  • Change from baseline functionality at 3 months according to the Instrumental Activities of Daily Living Scale (IADL). [ Time Frame: From baseline to assessment at time point 90 days after discharge date. ] [ Designated as safety issue: No ]
    Change from baseline functionality at 3 months after discharge date will be assessed at time point 90 days from hospital discharge date, according to the 8-item Instrumental Activities of Daily Living Scale (IADL).

  • Change from baseline functionality at 6 months according to the Instrumental Activities of Daily Living Scale (IADL). [ Time Frame: From baseline to assessment at time point 180 days after discharge date. ] [ Designated as safety issue: No ]
    Change in functionality from baseline at 6 months after discharge date will be assessed at time point 180 days from hospital discharge date, according to the 8-item Instrumental Activities of Daily Living Scale (IADL).

  • Mortality during hospital admission. [ Time Frame: From 1st day of admission to the day that in-hospital death from any cause is documented admission, assessed up to hospital discharge. ] [ Designated as safety issue: No ]
    In-hospital mortality is reflected by the number of deaths (percentage of the total number of subjects included in the study) during hospital admission, assessed up to 30 days from admission date.

  • Overall mortality [ Time Frame: From date of randomization until the date death from any cause is documented, assessed up to 180 days from hospital discharge date. ] [ Designated as safety issue: No ]
    Overall mortality is reflected by the number of deaths (percentage of the total number of subjects included in the study) from the date of randomization until the assessment time point at 180 days from admission date.


Estimated Enrollment: 780
Study Start Date: November 2012
Estimated Study Completion Date: May 2015
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Investigational medicinal product
Haloperidol 1 mg twice daily at 12am and 20pm
Drug: Haloperidol
An oral dosage of 1mg twice daily at 12am and 8pm.
Other Names:
  • Haldol
  • Antipsychotic agent
  • Dopamine antagonist
  • Butyrophenone
Placebo Comparator: Placebo group
Placebo 1 mg twice daily at 12am and 20pm
Drug: Placebo
An oral dosage of 1mg twice-daily at 12am and 8 pm.
Other Name: Placebo

  Hide Detailed Description

Detailed Description:

To address the aforementioned objectives, we propose a multicentre, randomized, double-blind, placebo-controlled intervention trial.

Eligible patients or their proxies will be verbally informed by the executive investigator on the content of the study, benefits and risks, and will receive a patient information folder on the nature of the study (version number, see appendix). The time to consider participation to the trial will be 2 hours maximum. Subsequently the patient or their proxy is asked for informed consent. After obtaining written informed consent, subjects are screened for delirium-risk by the executive investigator administrating three delirium-risk questions to the patients or their care-givers, as recommended by the Dutch Safety Management (VMS) program:

  1. Do you have memory complaints?
  2. Did you need any help with activities of daily living in the past 24 hours?
  3. During previous illness or hospital admission(s), did you have periods of confusion?

One or more positive answers will identify an at-risk patient, who will be assigned a daily intervention with either low-dose haloperidol (an oral dosage of 1mg, twice-daily) or placebo by stratified randomization. The maximum intervention duration is 7 days. Hospital admission course of non at-risk patients according to the three VMS delirium-risk questions will be retrospectively assessed by medical chart review. Different study measurements will be collected on admission. A baseline ECG and standard ED laboratory will be done. Two additional blood samples of 10ml each will be drawn to determine haloperidol plasma levels and stored for future research. The investigator will assess baseline cognitive- and physical functioning on admission with different questionnaires and observational measures: the 6-item cognitive impairment test (CIT), the 6-item Index of Independence in Activities of Daily Living (ADL), the 8-item Instrumental Activities of Daily Living scale (IADL) and Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE-N). The presence of delirium in the ED will be established according to the CAM-ICU and DSM-IV criterial. During admission, all subjects will receive the same 'high standard delirium care' based on effective non-pharmacological delirium intervention methods. Additionally to the standard ward rounds, the investigator will visit the patient at least on day 2, 4, 6 en 8 for (extended) physical examination and to evaluate any possible side-effects related to the intervention. According to protocol, an ECG is performed 6 hours after the first intervention dose by nursing staff on request of the investigator. An ECG will be repeated at a 6-hour time-interval after every dose until a steady state is reached, when QTc > 420ms and ≤ 500ms on baseline ECG, or QTc prolongation > 25% from baseline. If QTc ≥ 500ms, the study medication will be discontinued. A list of QTC prolonging drugs contraindicated when using haloperidol (1st degree drug interactions, reason for action) is available and an a warning system is implemented in the medication prescription system.

Development of delirium symptoms during the study will be evaluated by the Delirium Observation Screening (DOS) scale, administered 3 times per day. When delirium is suspected based on a mean DOS scale score >3/24 hours, the diagnosis is established according to the DSM-IV criteria by either the geriatrician or psychiatrist.

In case of established delirium within the 7-day intervention period, administration of the assigned intervention is stopped since one of the primary endpoints (i.e. incidence) is reached. Unblinding will be performed immediately and the treating physician will further decide on the treatment of the patients' delirium. Nursing staff will perform the DOS score 3-times daily to assess the duration of delirium, according to protocol. In addition, the investigator will assess delirium duration and severity with the DRS-R-98 once-daily. Both the DOS scale and DRS-R-98 are performed until delirium symptoms resolve or if participation in the study is no longer possible due to for example transfer to an other facility, ICU/CCU admission or death.

If no delirium symptoms develop within the 7-day intervention period, administration of the assigned intervention treatment is stopped after 7 days. If the subject is still admitted, evaluation of delirium symptoms will be done according to protocol with a DOS score 3-times daily . If delirium symptoms develop, and is diagnosed according to the DSM-IV criteria, the DRS-R-98 is administered once daily to until delirium symptoms diminish. Further admission course will be evaluated by retrospective analysis of patients' charts.

In patients discharged home within the 7-day intervention period, the intervention is stopped one day before discharge since it takes approximately 12 - 38 hours to eliminate half of the originally administered oral haloperidol dose. These patients will be subjected to en extended physical examination on the day of discharge to evaluate any possible side-effects related to the intervention. If this is not possible, and the patient is discharged after the first intervention dose of that day, the patient will be phoned 24 hours after discharge by the investigator to check for possible side-effects. In addition, the independent physician and researchers can be contacted for questions any time.

At the end of the study, all subjects' charts will be reviewed by one of the investigators.

In case of established delirium within the 7-day intervention period or when clinically relevant side-effects (possibly) related to the intervention have occured, unblinding will be done. Unblinding is possible 24 hours per day, 7 days a week through the contact number on the study medication packing. Procedures and argumentation will be documented and signed by the person performing the unblinding.

During the follow-up period, an executive investigator will contact the subject and/or proxy by telephone, respectively at 3- and 6-months after hospital discharge, to evaluate physical function at that time with the ADL and IADL scale. Also information on hospital re-admission(s), the need for additional (health)care or (permanent) institutionalization after hospital discharge and death are reported. Each telephone conversation will take an estimated 20 minutes.

  Eligibility

Ages Eligible for Study:   70 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Patients aged 70 years or over;
  • The patient is at increased risk for developing in-hospital delirium on admission according to one or more positive answers on the VMS delirium-risk questions;
  • The patient or proxy is able to provide written informed consent;
  • The patient or proxy speaks either Dutch or English;
  • The patient is admitted to the hospital for an internal or surgical specialty.

Exclusion Criteria:

  • Patients presenting in the ED with delirium according to the DSM-IV criteria;
  • Patients with clinically significant cardiac disorders: QTc interval prolongation (QTc ≥ 500ms), recent acute myocardial infarction, uncompensated heart failure (working diagnosis), acute coronary syndrome (ACS), arrhythmias treated with class IA and III antiarrhythmic medicinal products, history of ventricular arrhythmia, history of torsades, clinically significant bradycardia, second or third degree heart block, uncorrected hypokalaemia (potassium level 3.0 or lower);
  • Patients with vascular dementia;
  • Patients with Lewy Body dementia;
  • Patients with Parkinson dementia;
  • Patients with (a history of) hypokinetic movement disorders;
  • Patients with (a history of) malignant neuroleptic syndrome;
  • Patients with (a history of) serotonergic syndrome;
  • Patients with (a history of) central anticholinergic syndrome;
  • Patients who will be admitted to the oncology ward;
  • Patients who are enrolled in other medical- or drug studies;
  • Patients using QT prolonging drugs and/or medications of which concomitant use with haloperidol is contraindicated (clinically relevant drug interactions, 1st degree, listed in the appendix of the study protocol);
  • Patients using antipsychotics other than benzodiazepines;
  • Patients using intramuscular neuroleptic depot injections;
  • Epilepsy;
  • Substance abuse and dependence (DSM-IV criteria)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01530308

Contacts
Contact: P. WB Nanayakkara, Dr p.nanayakkara@vumc.nl

Locations
Netherlands
Jeroen Bosch Ziekenhuis Recruiting
Den Bosch, Brabant, Netherlands, 5223 GZ
Contact: R J van Marum, MD PhD Prof    0031 73 553 20 00    r.v.marum@jbz.nl   
Contact: A M van Strien, MD    0031 73 553 20 00    a.v.strien@jbz.nl   
Principal Investigator: Rob J van Marum, MD PhD Prof         
Sub-Investigator: Astrid M van Strien, MD         
Spaarne Ziekenhuis Not yet recruiting
Hoofddorp, Noord Holland, Netherlands, 2134 TM
Contact: A M Lagaay, Dr       ALagaay@spaarneziekenhuis.nl   
Principal Investigator: G Lagaay, MD PhD         
VUmc Recruiting
Amsterdam, Noord-Holland, Netherlands, 1007 MB
Contact: P WB Nanayakkara, MD PhD       p.nanayakkara@vumc.nl   
Contact: E JM Schrijver, MD       ej.schrijver@vumc.nl   
Principal Investigator: O J de Vries, MD         
Rijnland Ziekenhuis Recruiting
Leiderdorp, Netherlands, 2353 GA
Contact: Sander Anten, MD       s.anten@rijnland.nl   
Contact: Esther Kuipéri, MD       e.kuiperi@rijnland.nl   
Principal Investigator: Sander Anten, MD         
Isala Klinieken Recruiting
Zwolle, Netherlands, 8011 JW
Contact: A M Kamper, MD PhD       a.m.kamper@isala.nl   
Contact: S HA Diepeveen, MD PhD       s.h.a.diepeveen@isala.nl   
Principal Investigator: A M Kamper, MD PhD         
Sponsors and Collaborators
VU University Medical Center
Investigators
Principal Investigator: P WB Nanayakkara, Md, PhD VU University Medical Center
Principal Investigator: O J de Vries, MD VU University Medical Center
Principal Investigator: P M Bet, Pharm D VU University Medical Center
  More Information

Additional Information:
No publications provided

Responsible Party: Prabath W.B. Nanayakkara, Principal Investigator, VU University Medical Center
ClinicalTrials.gov Identifier: NCT01530308     History of Changes
Other Study ID Numbers: NL38027.029.12, 2011-004762-15, 3207
Study First Received: December 22, 2011
Last Updated: June 10, 2014
Health Authority: Netherlands: Medical Ethics Review Committee (METC)

Keywords provided by VU University Medical Center:
Delirium

Additional relevant MeSH terms:
Delirium
Emergencies
Confusion
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Disease Attributes
Pathologic Processes
Haloperidol
Haloperidol decanoate
Antipsychotic Agents
Dopamine Antagonists
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Gastrointestinal Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Dyskinesia Agents

ClinicalTrials.gov processed this record on July 24, 2014