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Dexmedetomidine Sublingual Film for the Management of Agitation in Delirium: Safety and Preliminary Efficacy

Primary Purpose

Delirium

Status
Unknown status
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Dexmedetomidine sublingual film
Sponsored by
Jeff C. Huffman, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Delirium focused on measuring agitation, delirium, dexmedetomidine

Eligibility Criteria

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

Inclusion Criteria:

  • Adults hospitalized on a medical or surgical intensive care unit at MGH
  • Diagnosis of delirium, assessed according to DSM-5 criteria (DSM-5)
  • Body mass index (BMI) between 18 and 30 kg/m2, inclusive, at screening
  • Weight at least 60 kg (132 pounds), at screening
  • In the opinion of the study and clinical teams, sufficiently physically healthy to receive dexmedetomidine sublingual film

Exclusion Criteria:

  • Per medical record or team report, diagnoses of:

    • Dementia
    • Significant traumatic brain injury
    • History of stroke, with persistent neurologic deficits
  • Presence of any of the following cardiovascular comorbidities

    • Sick sinus syndrome
    • A resting heart rate of < 55 beats per minutes or systolic blood pressure (BP) <100 mmHg or >160 mmHg or diastolic BP <70 mmHg or ˃ 95 mmHg at enrollment and prior to dosing.
    • Evidence of cardiac ischemia on a 12-lead electrocardiogram (ECG)
    • Corrected QT interval of > 450 msec
    • Presence of a permanent pacemaker device
  • Per medical record (notes, current medications, flowsheets):

    • Second degree (or greater) Atrioventricular (AV) block without a pacemaker
    • Known allergy or adverse reaction to dexmedetomidine
    • Current use of dexmedetomidine
  • Inability to take sublingual dexmedetomidine due to severe agitation, neurological impairment, nil per os (NPO) status, or other cause.
  • Hepatic impairment (liver function tests > 3 times the upper limit of normal)
  • Severe renal impairment (glomerular filtration rate (GFR) < 30 ml/min or on dialysis)
  • Weight < 60 kg
  • Pregnancy (in women; tested with serum or urine human chorionic gonadotropin [hCG])
  • Non-fluency in English
  • Prior enrollment in the study, with receipt of study medication, during the current or a previous hospitalization

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Experimental

    Arm Label

    20 mcg

    60 mcg

    Arm Description

    Participants randomized to the 20mcg group will receive 20mcg of dexmedetomidine sublingual film every 30 minutes, if they continue to have agitation and do not meet any cardiovascular stopping criteria. The maximum dosing for this arm is 80mcg.

    Participants randomized to the 60mcg group will receive 60mcg of dexmedetomidine sublingual film every 30 minutes, if they continue to have agitation and do not meet any cardiovascular stopping criteria. The maximum dosing for this arm is 240mcg.

    Outcomes

    Primary Outcome Measures

    Change in Heart Rate
    Heart rate will be assessed participant's flowsheet or using the telemetry monitor for the 6 hours following the initial medication administration.
    Change in Blood Pressure
    Blood pressure will be assessed participant's flowsheet or using the telemetry monitor/automated blood pressure cuff for the 6 hours following the initial medication administration.
    Change in Oxygen Saturation
    Oxygen saturation will be assessed participant's Epic flowsheet or using the telemetry monitor/pulse oximter for the 6 hours following the initial medication administration.
    Change in QTc Interval
    An ECG will be performed intermittently over the 6 hour monitoring period, and QTc will be calculated using the Fridericia formula.
    Self-reported Side Effects
    Incidence of side effects reported for dexmedetomidine in post-marketing surveillance

    Secondary Outcome Measures

    Change in Agitation
    Agitation will be measured by the Richmond Agitation-Sedation Scale (RASS). RASS is a 10-point scale ranging from -5 to +4, with a more positive score indicating increased agitation.
    Change in Delirium Severity
    Delirium severity will be measured by the Delirium Rating Scale-revised-98 (DRS-R-98). The maximum possible score for severity items is 39, while the maximum total score is 46. Higher scores indicate more severe delirium; score of 0 indicates no delirium.
    Time to resolution of agitation
    Amount of time from the initial dexmedetomidine administration until agitation resolves measured by RASS score < 1

    Full Information

    First Posted
    April 25, 2020
    Last Updated
    May 6, 2020
    Sponsor
    Jeff C. Huffman, MD
    Collaborators
    BioXcel Therapeutics Inc
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04382170
    Brief Title
    Dexmedetomidine Sublingual Film for the Management of Agitation in Delirium: Safety and Preliminary Efficacy
    Official Title
    Dexmedetomidine Sublingual Film for the Management of Agitation in Delirium: Safety and Preliminary Efficacy
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    May 2020
    Overall Recruitment Status
    Unknown status
    Study Start Date
    June 2020 (Anticipated)
    Primary Completion Date
    June 2021 (Anticipated)
    Study Completion Date
    June 2021 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor-Investigator
    Name of the Sponsor
    Jeff C. Huffman, MD
    Collaborators
    BioXcel Therapeutics Inc

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    The investigator will examine the safety, tolerability, optimal dose, and preliminary efficacy of dexmedetomidine sublingual film in a randomized, double-blind, controlled trial in 40 hospitalized patients with hyperactive delirium (i.e., delirium with agitation) in the Intensive Care Unit (ICU) setting. Specific Aim #1 (safety and tolerability): To examine the incidence of cardiovascular and other side effects following the administration of dexmedetomidine sublingual film in patients hospitalized in the ICU with delirium and agitation in a randomized, double-blind trial (total N=80 patients with delirium [with or without agitation], with a goal of administering dexmedetomidine to at least 40 participants with agitation). Hypothesis: Dexmedetomidine sublingual film will be associated with hypotension and/or bradycardia requiring clinical intervention in ≤ 20% (8 of 40) participants. Dexmedetomidine will not be associated with QTc prolongation or non-cardiac adverse events. Specific Aim #2 (preliminary efficacy): To examine the impact of dexmedetomidine sublingual film on agitation and delirium severity. Hypothesis: Dexmedetomidine will lead to reductions in agitation and delirium severity during the follow-up period (co-primary endpoints = 1 and 2 hours post-administration). Specific Aim #3 (optimal dosing): To identify the minimum dose that is effective at reducing agitation and delirium severity without causing significant side effects. Hypothesis: Participants receiving doses of 60 mcg of dexmedetomidine will have a faster time to a reduction in agitation and greater reductions in delirium severity than participants receiving 20 mcg of dexmedetomidine.
    Detailed Description
    Study Intervention Participants will be randomized to receive either 20 mcg or 60 mcg of dexmedetomidine sublingually. Participants will receive repeat dosing every 30 minutes for up to three additional doses, leading to maximum doses of 80 mcg and 240 mcg, respectively. Both investigators and clinicians will be blind to the participant's group, with only the study pharmacist aware of the dose of medication on the films. Baseline monitoring: Following enrollment, the study team will record baseline measures of heart rate, blood pressure, and oxygen saturation. An electrocardiogram (ECG) will be performed, and agitation and delirium severity will be measured. Medication administration: Dexmedetomidine sublingual film will be administered by the study physician or study nurse as per the manufacturer's instructions. Dexmedetomidine administration will be repeated every 30 minutes if the participant continues to have agitation and does not meet any cardiovascular stopping criteria. Monitoring for side effects: Heart rate, blood pressure, oxygen saturation, use of supplemental oxygen, and use of pressors will be monitored continuously and recorded every 30 minutes for the 6 hours following the initial medication administration (baseline; Time 0). An ECG will be performed at 1.5, 3, 4.5, and 6 hours, and QTc will be calculated using the Fridericia formula. Study staff will also monitor the participant and speak with nursing staff at 6 hours to assess for any other side effects/complaints the patient may have had during the time since medication administration. Monitoring of agitation and delirium severity: Agitation will be measured every 30 minutes and delirium severity at hours 1, 2, 3, 4, and 6. Study Endpoints Safety and Tolerability (Aim #1) The investigators will examine changes in heart rate, blood pressure, oxygen saturation, and QTc interval from baseline to the follow-up timepoints, as well as the incidence of self-reported and clinician-reported side effects during the 6-hour post-medication interval. They also will record the total dosage of medication each participant received and examine whether medication dose was associated with the incidence of side effects. Preliminary Efficacy (Aim #2) The investigators will assess changes in agitation and delirium from baseline to the follow-up timepoints. One and two hours following medication administration will be considered the co-primary timepoints for these efficacy measures. They also will record the total dosage of medication each participant received and examine whether medication dose was associated with a reduction in agitation and delirium severity. Minimum Dose of Administration (Aim #3) The investigators will measure the amount of time from the initial dexmedetomidine administration until agitation resolves. Then, they will compare between-group differences in time to agitation resolution, changes in agitation and delirium severity, and the incidence of side effects. The optimal dose will be chosen based on the dose that leads to the quickest resolution of agitation without leading to clinically significant side effects.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Delirium
    Keywords
    agitation, delirium, dexmedetomidine

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Model Description
    This study will be a randomized, controlled, 2-arm, double-blinded trial.
    Masking
    ParticipantCare ProviderInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    80 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    20 mcg
    Arm Type
    Active Comparator
    Arm Description
    Participants randomized to the 20mcg group will receive 20mcg of dexmedetomidine sublingual film every 30 minutes, if they continue to have agitation and do not meet any cardiovascular stopping criteria. The maximum dosing for this arm is 80mcg.
    Arm Title
    60 mcg
    Arm Type
    Experimental
    Arm Description
    Participants randomized to the 60mcg group will receive 60mcg of dexmedetomidine sublingual film every 30 minutes, if they continue to have agitation and do not meet any cardiovascular stopping criteria. The maximum dosing for this arm is 240mcg.
    Intervention Type
    Drug
    Intervention Name(s)
    Dexmedetomidine sublingual film
    Other Intervention Name(s)
    Precedex
    Intervention Description
    Dexmedetomidine sublingual film for the management of agitation in hospitalized patients with delirium.
    Primary Outcome Measure Information:
    Title
    Change in Heart Rate
    Description
    Heart rate will be assessed participant's flowsheet or using the telemetry monitor for the 6 hours following the initial medication administration.
    Time Frame
    Baseline, Medication Administration (Hour 0), Hour 0.5, Hour 1, Hour 1.5, Hour 2, Hour 2.5, Hour 3, Hour 3.5, Hour 4, Hour 4.5, Hour 5, Hour 5.5, Hour 6
    Title
    Change in Blood Pressure
    Description
    Blood pressure will be assessed participant's flowsheet or using the telemetry monitor/automated blood pressure cuff for the 6 hours following the initial medication administration.
    Time Frame
    Baseline, Medication Administration (Hour 0), Hour 0.5, Hour 1, Hour 1.5, Hour 2, Hour 2.5, Hour 3, Hour 3.5, Hour 4, Hour 4.5, Hour 5, Hour 5.5, Hour 6
    Title
    Change in Oxygen Saturation
    Description
    Oxygen saturation will be assessed participant's Epic flowsheet or using the telemetry monitor/pulse oximter for the 6 hours following the initial medication administration.
    Time Frame
    Baseline, Medication Administration (Hour 0), Hour 0.5, Hour 1, Hour 1.5, Hour 2, Hour 2.5, Hour 3, Hour 3.5, Hour 4, Hour 4.5, Hour 5, Hour 5.5, Hour 6
    Title
    Change in QTc Interval
    Description
    An ECG will be performed intermittently over the 6 hour monitoring period, and QTc will be calculated using the Fridericia formula.
    Time Frame
    Baseline, Hour 1.5, Hour 3, Hour 4.5, Hour 6
    Title
    Self-reported Side Effects
    Description
    Incidence of side effects reported for dexmedetomidine in post-marketing surveillance
    Time Frame
    Hour 6
    Secondary Outcome Measure Information:
    Title
    Change in Agitation
    Description
    Agitation will be measured by the Richmond Agitation-Sedation Scale (RASS). RASS is a 10-point scale ranging from -5 to +4, with a more positive score indicating increased agitation.
    Time Frame
    Baseline, Hour 0.5, Hour 1, Hour 1.5, Hour 2, Hour 2.5, Hour 3, Hour 3.5, Hour 4, Hour 4.5, Hour 6
    Title
    Change in Delirium Severity
    Description
    Delirium severity will be measured by the Delirium Rating Scale-revised-98 (DRS-R-98). The maximum possible score for severity items is 39, while the maximum total score is 46. Higher scores indicate more severe delirium; score of 0 indicates no delirium.
    Time Frame
    Baseline, Hour 1, Hour 2, Hour 3, Hour 4, Hour 6
    Title
    Time to resolution of agitation
    Description
    Amount of time from the initial dexmedetomidine administration until agitation resolves measured by RASS score < 1
    Time Frame
    Hour 6

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Adults hospitalized on a medical or surgical intensive care unit at MGH Diagnosis of delirium, assessed according to DSM-5 criteria (DSM-5) Body mass index (BMI) between 18 and 30 kg/m2, inclusive, at screening Weight at least 60 kg (132 pounds), at screening In the opinion of the study and clinical teams, sufficiently physically healthy to receive dexmedetomidine sublingual film Exclusion Criteria: Per medical record or team report, diagnoses of: Dementia Significant traumatic brain injury History of stroke, with persistent neurologic deficits Presence of any of the following cardiovascular comorbidities Sick sinus syndrome A resting heart rate of < 55 beats per minutes or systolic blood pressure (BP) <100 mmHg or >160 mmHg or diastolic BP <70 mmHg or ˃ 95 mmHg at enrollment and prior to dosing. Evidence of cardiac ischemia on a 12-lead electrocardiogram (ECG) Corrected QT interval of > 450 msec Presence of a permanent pacemaker device Per medical record (notes, current medications, flowsheets): Second degree (or greater) Atrioventricular (AV) block without a pacemaker Known allergy or adverse reaction to dexmedetomidine Current use of dexmedetomidine Inability to take sublingual dexmedetomidine due to severe agitation, neurological impairment, nil per os (NPO) status, or other cause. Hepatic impairment (liver function tests > 3 times the upper limit of normal) Severe renal impairment (glomerular filtration rate (GFR) < 30 ml/min or on dialysis) Weight < 60 kg Pregnancy (in women; tested with serum or urine human chorionic gonadotropin [hCG]) Non-fluency in English Prior enrollment in the study, with receipt of study medication, during the current or a previous hospitalization
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Jeff C. Huffman, MD
    Phone
    617-724-2910
    Email
    jhuffman@mgh.harvard.edu
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Jeff C Huffman, MD
    Organizational Affiliation
    Massachusetts General Hospital
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No

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    Dexmedetomidine Sublingual Film for the Management of Agitation in Delirium: Safety and Preliminary Efficacy

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