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Sub-Lingual Dexmedetomidine in Agitation Associated With Dementia (TRANQUILITY)

Primary Purpose

Agitation,Psychomotor, Dementia

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Sublingual film containing Dexmedetomidine

Sublingual Placebo Film

About this trial

This is an interventional treatment trial for Agitation,Psychomotor

Eligibility Criteria

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

Inclusion Criteria:

Male and female patients 65 years and older.
Patients who have dementia and a history of acute agitation.
History of agitation that requires intervention or impairs social or daily activities
Patients who meet International Psychogeriatric Association (IPA) diagnostic criterion for agitation.
Patients with a total score of ≥ 8 on the Pittsburgh Agitation Scale (PAS).
Patients who have a score of ≥ 2 on at least 1 of the 4 items on the Pittsburgh Agitation Scale (PAS).
Patients who read, understand and provide written informed consent, or who have a Legally Authorized Representative (LAR).
Patients who are in good general health.

Exclusion Criteria:

For Part B: Patients with dementia associated with Parkinson's disease and/or Lewy Body Disease, if etiology of dementia is known.
Patients with agitation caused by acute intoxication.
Patients treated within 4 hours prior to study drug administration with benzodiazepines, other sedatives, hypnotics or oral or short-acting intramuscular antipsychotics must be excluded.
Treatment with alpha-1 noradrenergic blockers, alpha adrenergic antagonists within 8 hours prior to dosing.
No new chronic medications initiated in the past 14 days prior to screening excluding over-the-counter products taken sporadically.
Patients at significant risk of harm to themselves or others
Patients considered medically unstable or in recovery
Patients with history of clinically significant syncope or syncopal attacks, orthostatic hypotension within the past 2 years, current evidence of hypovolemia, orthostatic hypotension.
Cohort 3 only: Patients who are taking nitrates or beta blockers shall be excluded. Any other anti-hypertensives should be maintained in the course of the study.
Patients who have received an investigational drug within 30 days prior to the current agitation episode must be excluded.
Patients experiencing clinically significant pain, per Investigator.
Cohort 3 only: Patients who are a high fall risk assessed via the Johns Hopkins Fall Risk Assessment (total score >13) or during the 1-week safety observation period
Pregnancy

Sites / Locations

BioXcel Clinical Research Site
BioXcel Clinical Research Site
BioXcel Clinical Research Site
BioXcel Clinical Research Site
BioXcel Clinical Research Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Arm Label

Cohort 1- 30 Micrograms

Cohort 2- 60 Micrograms

Cohort 3- 90 Micrograms

Part B Cohort

Arm Description

Cohort 1 consists of 10 patients out of whom 8 patients receive 30 Micrograms film and the remaining 2 patients receive a placebo

Cohort 2 consists of 10 patients out of whom 8 patients receive 60 Micrograms film and the remaining 2 patients receive a placebo. Additional 20 subjects receive 60 Micrograms or placebo.

Cohort 3 consists of 10 patients out of whom 8 patients receive 90 Micrograms film and the remaining 2 patients receive a placebo

Part B cohort consists 46 subjects receiving 40 Micrograms or placebo

Outcomes

Primary Outcome Measures

Mean Change From Baseline in Positive and Negative Syndrome Scale-Excited Component (PEC) Total Score

The change in PEC score was evaluated at 2 hours following the administration of the BXCL501 60 mcg, and BXCL501 30 mcg (for Part A) and BXCL501 40 mcg (for Part B) versus placebo. PEC is the sum of 5 subscales (poor impulse control, tension, hostility, uncooperativeness, and excitement, each subscale ranging from 1 to 7) and thus ranges from 5 to 35. Change from baseline (pre-dose) PEC total score, with negative values is in favor of improvement.

Number of Patients With Adverse Events

The safety and tolerability of single doses of BXCL501 was determined in treatment of acute agitation associated with dementia.

Secondary Outcome Measures

Change in Pittsburgh Agitation Scale (PAS) Total Score From Baseline

The onset and magnitude of calming effects of different doses of BXCL501 on symptoms of acute agitation associated with dementia was described as measured by the PAS. The PAS is an instrument that measured 4 behaviors namely: aberrant vocalization, motor agitation, aggressiveness and resisting to care. The patients are evaluated on a scale of 0 to 4, where 0 indicated no agitation and 4 indicated highest form of agitation. The PAS total score ranges from 0 to 16. Higher scores mean a worse outcome. Change in value of PAS total score, with negative value indicated the improvement in condition of the patients.

Changes in Agitation-Calmness Evaluation Scale (ACES) Score From Baseline

To evaluate the change in the total score of ACES from baseline to 8 hours post administration of 30 mcg, 60 mcg and 40 mcg compared to placebo. The ACES is a single item measure rating overall agitation and sedation which ranges from 1 to 9, where 1 indicates marked agitation, 2 - moderate agitation; 3 - mild agitation; 4 - normal behavior; 5 - mild calmness; 6 - moderate calmness; 7 - marked calmness; 8 - deep sleep; and 9 - unarousable. Change from baseline (pre-dose) ACES total score, with negative values in favor of improvement.

Changes in Positive and Negative Syndrome Scale (PANSS) Excited Component (PEC) Total Score From Baseline

The change in PEC score was evaluated following the administration of the BXCL501 60 mcg, and BXCL501 30 mcg (for Part A) and BXCL501 40 mcg (for Part B) versus placebo. PEC is the sum of 5 subscales (poor impulse control, tension, hostility, uncooperativeness, and excitement, each subscale ranging from 1 to 7) and thus ranges from 5 to 35. Change from baseline (pre-dose) PEC total score, with negative values is in favor of improvement.

Number of Patients at Each Dose Who Achieve a 40% Reduction From Baseline in PEC Total Score at 2 Hours Post-dose ("Responders")

The Number of patients who achieved a 40%reduction in total PEC score from baseline at 2 hours following administration of BXCL501 30 mcg, 60 mcg (for Part A) and BXCL501 40 mcg (for Part B) compared to placebo were evaluated. Responder defined as achieving >= 40% reduction in PEC from baseline (pre-dose). The change from baseline in (pre-dose) PEC total score is presented for the Primary Outcome above.

Change in Clinician Global Impression of Severity (CGI-S) Agitation Score From Baseline

The CGI-S was based upon the severity of agitation. It was assessed based on the following scale: 0 = Not assessed; 1 = Normal not at all symptomatic; 2 = Minimally symptomatic- few or mild symptoms -little interference with patients functioning; 3 = Mildly symptomatic-low level of symptoms-little interference in social functioning; 4 = Moderately symptomatic-some prominent symptoms-some interference in functioning; 5 = Markedly symptomatic-significant symptoms with very substantial interference in functioning; 6 = Severely symptomatic- very marked symptoms make it difficult for patients to engage with others; 7 = Among the most extremely symptomatic patients-extreme symptoms -patient is incapacitated or highly dangerous to self or others requires extra care and supervision. The higher the score, the higher is the severity of the agitation and lesser the score, the lower the agitation. Change from baseline CGIS total score, with negative values in favor of improvement.

Clinical Global Impression - Improvement (CGI-I) Agitation Score

To evaluate the CGI-I agitation score at 30 minutes, 1 hour, 2 hours, and 8 hours after administration of 30 mcg, 60 mcg and 40 mcg of BXCL501 compared to placebo. The CGI-I scores range from 1 to 7 comprise of 0 = Not assessed (missing), 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse. The lower score (1) indicated the improvement in the condition of patient and higher score (7) indicates the worsening of the condition. Straight CGI-I total score, with lower values in favor of improvement.

Change in Cohen Mansfield Agitation Inventory (CMAI) Total Score From Baseline

To evaluate the change in Cohen Mansfield Agitation Inventory (CMAI) total score from baseline after 2 hour and on Day 7 post administration of 30 mcg, 60 mcg and 40 mcg BXCL501 compared to placebo. The CMAI is a rating which is comprised of 29 behaviors each rated on a 7-point scale of frequency. A total CMAI score is obtained by summing all the individual items, giving a range from 29 to 203. Change from baseline (pre-dose) CMAI total score, with negative values in favor of improvement in the condition of the patients.

Number of Patients With Event "Time Taken for Medication to Dissolve"

To evaluate the time taken for BXCL501 30 mcg, 60mcg, 90 mcg and 40 mcg compared to placebo to dissolve which was measured after 30 minutes of administration.

Number of Patients Showing Negative Reaction to Sublingual Film in the Examiner's Opinion

To evaluate the number patient showing negative reactions to sublingual film by assessing the buccal at 30 minutes, 2 hours, 4 hours and 24 hours post administration of 30mcg, 60 mcg, 40 mcg and 90 mcg v/s placebo. The larger number of patients reporting negative reaction, the lesser is the reliability of the drug.

Part B: Change From Baseline in the Total Score of 3 Supplementary Items of Positive and Negative Syndrome Scale (PANSS)

To evaluate the change in PANSS Supplementary Items Total Score from Baseline to 2 hours post administration of 40 mcg of BXCL501 compared to placebo. PANSS Supplementary Items: The total score (sum score of anger, difficulty in delaying gratification, and affective lability) ranges from 3 to 21. The higher score indicates the worsening of the condition and lower score indicates the improvement of the condition of the patient. Change from baseline (pre-dose) PANSS Supplementary Items total score, with negative values in favor of improvement.

Full Information

NCT ID

NCT04251910

First Posted

January 28, 2020

Last Updated

August 28, 2023

Sponsor

BioXcel Therapeutics Inc

Collaborators

Cognitive Research Corporation

1. Study Identification

Unique Protocol Identification Number

NCT04251910

Brief Title

Sub-Lingual Dexmedetomidine in Agitation Associated With Dementia

Acronym

TRANQUILITY

Official Title

A Phase Ib/II, Multicenter, Randomized, Double Blind, Placebo Controlled, Ascending Dose Finding, Efficacy, Pharmacokinetic and Safety Study of BXCL501 In Agitation Associated With Dementia

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Completed

Study Start Date

December 27, 2019 (Actual)

Primary Completion Date

January 24, 2022 (Actual)

Study Completion Date

January 24, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

BioXcel Therapeutics Inc

Collaborators

Cognitive Research Corporation

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

This is an adaptive Phase 1b/2 trial design. It is randomized, double-blind, placebo-controlled, multiple ascending dose study assessing efficacy, pharmacokinetics, safety and tolerability of BXCL-501 dosing in adult (65 years and older) males and females with acute agitation associated with dementia. Evaluation of 3 doses are planned.

Detailed Description

This is a Phase 1b/2 randomized, double-blind, placebo controlled, ascending dose finding study assessing efficacy, pharmacokinetics, safety, and tolerability of BXCL501 with 3 dosing groups in adult (65 years and older) males and females with acute agitation associated with all forms of dementia. Evaluation of three (3) doses of sublingual BXCL 501 are planned. Cohort 1, Cohort 2 and Cohort 3 will be given 30µg, 60µg and 90µg dose respectively of BXCL501 or placebo. Subjects assigned to Cohort 3 will participate in a 1-week safety observation before being enrolled. This is an adaptive design as doses selected for testing may be different from these, based upon safety reviews. Doses lower or higher may be chosen to test, up to 180µg, and additional subjects may be added to a cohort. BXCL501 films may be divided in half if needed to deliver half-dose strengths. At least 30 subjects (10 per cohort) will be enrolled at up to 3 study sites in the United States. In Part B a total of 46 subjects will receive BXCL501 40 μg or matching placebo film. The effects of BXCL 501 on acute agitation will be assessed by the following scales: Pittsburgh Agitation Scale (PAS), the PANSS-EC (PEC), Cohen-Mansfield Agitation Inventory (CMAI), CGI-Severity for Agitation and CGI Improvement for Agitation. Adverse Events (AEs), clinical laboratory tests, ECG, and vital signs will be monitored, and all observed.

6. Conditions and Keywords

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

Agitation,Psychomotor, Dementia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) This is a double-blind study. Due to the nature of the drug, the pharmacist and the drug administrator will both be aware of the treatment. They have no other responsibility in the trial

Allocation

Randomized

Enrollment

100 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1- 30 Micrograms

Arm Type

Active Comparator

Arm Description

Cohort 1 consists of 10 patients out of whom 8 patients receive 30 Micrograms film and the remaining 2 patients receive a placebo

Arm Title

Cohort 2- 60 Micrograms

Arm Type

Active Comparator

Arm Description

Cohort 2 consists of 10 patients out of whom 8 patients receive 60 Micrograms film and the remaining 2 patients receive a placebo. Additional 20 subjects receive 60 Micrograms or placebo.

Arm Title

Cohort 3- 90 Micrograms

Arm Type

Active Comparator

Arm Description

Cohort 3 consists of 10 patients out of whom 8 patients receive 90 Micrograms film and the remaining 2 patients receive a placebo

Arm Title

Part B Cohort

Arm Type

Active Comparator

Arm Description

Part B cohort consists 46 subjects receiving 40 Micrograms or placebo

Intervention Type

Drug

Intervention Name(s)

Sublingual film containing Dexmedetomidine

Other Intervention Name(s)

BXCL501

Intervention Description

Sublingual film containing Dexmedetomidine

Intervention Type

Drug

Intervention Name(s)

Sublingual Placebo Film

Intervention Description

Sublingual placebo film that matches BXCL501

Primary Outcome Measure Information:

Title

Mean Change From Baseline in Positive and Negative Syndrome Scale-Excited Component (PEC) Total Score

Description

Time Frame

Baseline and 2 hours post-dose

Title

Number of Patients With Adverse Events

Description

The safety and tolerability of single doses of BXCL501 was determined in treatment of acute agitation associated with dementia.

Time Frame

Day 7 post dose

Secondary Outcome Measure Information:

Title

Change in Pittsburgh Agitation Scale (PAS) Total Score From Baseline

Description

Time Frame

Baseline and at 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, Day 3, Day 7 post-dose

Title

Changes in Agitation-Calmness Evaluation Scale (ACES) Score From Baseline

Description

Time Frame

Baseline and 1 hour, 2 hours, 4 hours, 8 hours post-dose

Title

Changes in Positive and Negative Syndrome Scale (PANSS) Excited Component (PEC) Total Score From Baseline

Description

Time Frame

Baseline and at 30 minutes, 1 hour, 4 hours, 8 hours, 24 hours, Day 3 and Day 7 post-dose

Title

Number of Patients at Each Dose Who Achieve a 40% Reduction From Baseline in PEC Total Score at 2 Hours Post-dose ("Responders")

Description

Time Frame

Baseline and 2 hours post-dose

Title

Change in Clinician Global Impression of Severity (CGI-S) Agitation Score From Baseline

Description

Time Frame

Baseline and at 2 hours, and 24 hours post-dose

Title

Clinical Global Impression - Improvement (CGI-I) Agitation Score

Description

Time Frame

30 minutes, 1 hour, 2 hours, 4 hours, 8 hours post-dose

Title

Change in Cohen Mansfield Agitation Inventory (CMAI) Total Score From Baseline

Description

Time Frame

Baseline and at 2 Hours and Day 7 post-dose

Title

Number of Patients With Event "Time Taken for Medication to Dissolve"

Description

To evaluate the time taken for BXCL501 30 mcg, 60mcg, 90 mcg and 40 mcg compared to placebo to dissolve which was measured after 30 minutes of administration.

Time Frame

At 30 minutes post-dose

Title

Number of Patients Showing Negative Reaction to Sublingual Film in the Examiner's Opinion

Description

Time Frame

At 30 minutes, 2 hours, 4 hours, 24 hours post dose

Title

Part B: Change From Baseline in the Total Score of 3 Supplementary Items of Positive and Negative Syndrome Scale (PANSS)

Description

Time Frame

Baseline and at 2 hours post-dose

10. Eligibility

Sex

All

Minimum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male and female patients 65 years and older. Patients who have dementia and a history of acute agitation. History of agitation that requires intervention or impairs social or daily activities Patients who meet International Psychogeriatric Association (IPA) diagnostic criterion for agitation. Patients with a total score of ≥ 8 on the Pittsburgh Agitation Scale (PAS). Patients who have a score of ≥ 2 on at least 1 of the 4 items on the Pittsburgh Agitation Scale (PAS). Patients who read, understand and provide written informed consent, or who have a Legally Authorized Representative (LAR). Patients who are in good general health. Exclusion Criteria: For Part B: Patients with dementia associated with Parkinson's disease and/or Lewy Body Disease, if etiology of dementia is known. Patients with agitation caused by acute intoxication. Patients treated within 4 hours prior to study drug administration with benzodiazepines, other sedatives, hypnotics or oral or short-acting intramuscular antipsychotics must be excluded. Treatment with alpha-1 noradrenergic blockers, alpha adrenergic antagonists within 8 hours prior to dosing. No new chronic medications initiated in the past 14 days prior to screening excluding over-the-counter products taken sporadically. Patients at significant risk of harm to themselves or others Patients considered medically unstable or in recovery Patients with history of clinically significant syncope or syncopal attacks, orthostatic hypotension within the past 2 years, current evidence of hypovolemia, orthostatic hypotension. Cohort 3 only: Patients who are taking nitrates or beta blockers shall be excluded. Any other anti-hypertensives should be maintained in the course of the study. Patients who have received an investigational drug within 30 days prior to the current agitation episode must be excluded. Patients experiencing clinically significant pain, per Investigator. Cohort 3 only: Patients who are a high fall risk assessed via the Johns Hopkins Fall Risk Assessment (total score >13) or during the 1-week safety observation period Pregnancy

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Robert Risinger, MD

Organizational Affiliation

BioXcel Therapeutics

Official's Role

Study Chair

Facility Information:

Facility Name

BioXcel Clinical Research Site

City

Homestead

State/Province

Florida

ZIP/Postal Code

33032

Country

United States

Facility Name

BioXcel Clinical Research Site

City

Miami Lakes

State/Province

Florida

ZIP/Postal Code

33016

Country

United States

Facility Name

BioXcel Clinical Research Site

City

Springfield

State/Province

Massachusetts

ZIP/Postal Code

01103

Country

United States

Facility Name

BioXcel Clinical Research Site

City

Caro

State/Province

Michigan

ZIP/Postal Code

48723

Country

United States

Facility Name

BioXcel Clinical Research Site

City

Toms River

State/Province

New Jersey

ZIP/Postal Code

08755

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Sub-Lingual Dexmedetomidine in Agitation Associated With Dementia

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