Dexmedetomidine Transdermal Systems (DMTS) Treatment for Agitation Associated With Dementia of the Alzheimer's Type

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of DMTS on frequency and severity of agitation associated with dementia of the Alzheimer's type, compared with placebo.

Detailed Description
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This is a randomized, double-blind, placebo-controlled, two application study of DMTS or matching placebo over a 4-day treatment period, followed 7 days later with the same treatment (active or placebo) for an additional 4-day treatment period. Eligible subjects will be screened up to 7 days prior to study start. Eligible subjects will be randomized 1:1:1 to treatment with 1 DMTS, 2 DMTS, or matching placebo.

Official Title
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A Double-Blind, Placebo-Controlled Evaluation of the Dexmedetomidine Transdermal Systems for Agitation Associated With Dementia of the Alzheimer's Type

Conditions
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Agitation

Intervention / Treatment
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* Drug: 12 cm2 - 2 Active DMTS Patches
* Drug: 6 cm2 - 1 Active and 1 Placebo DMTS Patches
* Drug: Placebo - 2 Placebo DMTS Patches


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily provide written informed consent (subject or legally authorized representative, or LAR). Male or female, 60+ years of age residing in a care facility. All subjects must have a diagnosis of dementia of probable Alzheimer's Disease (AD) based on National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria (2018). At least one item on the CMAI (using a 7-day lookback period) must receive a score of 4 or greater at Screening and at Baseline (Day -1). One or more episodes (using a 7-day lookback period) of agitation impairs social activities, requiring staff or medical intervention, or impairs ability for functional activities of daily living at Screening and at Baseline (Day -1). A minimum of 1 week with no change in medication prior to Screening. A score of 15 to 23 on the Mini-Mental State Examination (MMSE) at Screening. Female subjects are eligible only if the following apply: Not pregnant, not lactating, and not planning to become pregnant during the study or for 1 menstrual cycle thereafter. Surgically sterile; or at least 2 years postmenopausal; or have a monogamous partner who is surgically sterile; or have a same gender sex partner; or is using double-barrier contraception; or practicing abstinence; or using an insertable, injectable, transdermal, or combination oral contraceptive for 3 months prior to the study, during the study, and for 1 month following the study. Male subjects with female sex partners of childbearing potential must be surgically sterile or commit to use a reliable method of birth control during the study and for 1 month following the study. Reliable contraception is defined as: A tubal ligation, condom with spermicidal gel, an approved hormonal contraceptive such as oral contraceptives, emergency contraception used as directed, patches, implants, injections, rings or hormonally-impregnated intrauterine device (IUD), or an IUD. Have a body weight > 50 kg, and body mass index of 20 to 38 kg/m2, inclusive. Subject or LAR able to understand the study procedures, comply with all study procedures, and agree to participate in the study program for its full duration. Subject must live in residence for at least 7 days prior to screening and remain in residence through the completion of Follow Up assessments. Exclusion Criteria: Known sensitivity to dexmedetomidine or any excipient in the DMTS/placebo. Skin abnormality (eg, scar, tattoo) or unhealthy skin condition (eg, burns, wounds) at the DMTS/matching placebo application site, according to examination by the investigator at screening. Clinically significant abnormal clinical laboratory test value as determined by the investigator. Subjects with agitation caused by acute intoxication. Subjects with significant risk of suicide or homicide per investigator's assessment, or any patient with an answer of yes to Items 4 o 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS). History of deep vein thrombosis or factor V Leiden deficiency. History of or positive test results for the human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. Clinically significant history or clinically significant manifestation of any of the following, as determined by the investigator: a renal, hepatic, cardiovascular, metabolic, neurologic, or psychiatric condition; congestive heart failure, peptic ulcer, gastrointestinal bleeding, or other condition that may preclude participation in the study. History of physician-diagnosed migraine, frequent non-vascular headaches (> 5 per month), seizures, or are currently taking anticonvulsants. History of syncope or other syncopal attacks. Present and/or significant history of postural hypotension (determined through examination by the investigator or designee), or history of severe dizziness or fainting on standing in the opinion of the investigator. Evidence of a clinically significant 12-lead ECG abnormality. Average heart rate < 60 or > 100 bpm, systolic blood pressure (BP) < 90 or > 140 mmHg, or diastolic BP < 60 or > 90 mmHg, measured in 3 sequential positions (supine after 5 minutes; sitting after 2 minutes; and standing after 2 minutes) and after the sequence has been repeated 3 times. History of alcohol abuse or prescription/illicit drug abuse within the previous 5 years. Positive results on the urine drug screen or alcohol breath test indicative of drugs of abuse or alcohol use at screening. Receiving concurrent therapy that can interfere with the evaluation of efficacy or safety, such as any drug that in the investigator's opinion may exert significant synergistic interactions with dexmedetomidine. Use of any natural health products (including chaparral, comfrey, germander, jin bu huan, kava, pennyroyal, skullcap, St. John's wort, or valerian, and excluding vitamins or mineral supplements) within 7 days prior to study drug administration and throughout the study, unless in the opinion of the investigator or designee, the product will not interfere with the study procedures or data integrity or compromise the safety of the subject. Had symptoms of an upper respiratory tract infection within 7 days prior to dosing of the study drug. Utilized oral or injectable corticosteroids within 7 days prior to dosing of the study drug (intranasal and topical corticosteroid use during this time period is allowed). Received any investigational product within 30 days prior to dosing of the study drug. Received DMTS in a previous clinical trial. In the opinion of the investigator or designee, is considered unsuitable for study entry and/or is unlikely to comply with the study protocol for any reason.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects in each treatment group will receive a total of 4 patches/systems during the study (2 patches/system each dosing period). For the second dosing period, subjects will receive the same treatment administered as the first dosing period. An independent data monitoring committee will periodically review safety data to confirm the safety/tolerability of the dose or recommend a dose reduction. Subjects will reside in their care facility for the duration of the trial. The following assessments will be performed according to the Schedule of Events: agitation assessments (frequency and severity); sedation-level assessments; safety assessments (vital signs including oxygen saturation by pulse oximetry pulse oximetry (SpO2)); DMTS/matching placebo adhesion assessments; and skin irritation assessments. In addition, blood samples will be collected for determination of plasma concentrations of dexmedetomidine.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 12 cm2 - 2 Active DMTS Patches<br>2 Active DMTS patches will be applied to the upper back and worn for 4 days (96 hours) | Drug: 12 cm2 - 2 Active DMTS Patches<br>* 2 Active DMTS patches applied to the upper back followed 7 days later by another application of 2 Active DMTS patches. Each application will be worn for 4 days (96 hours)<br>|
| Active Comparator: 6 cm2 - 1 Active and 1 Placebo DMTS Patches<br>1 Active and 1 Placebo DMTS patches will be applied to the upper back and worn for 4 days (96 hours) | Drug: 6 cm2 - 1 Active and 1 Placebo DMTS Patches<br>* 1 Active and 1 Placebo DMTS patches applied to the upper back followed 7 days later by another application of 1 Active and 1 Placebo DMTS patches. Each application will be worn for 4 days (96 hours)<br>|
| Placebo Comparator: Placebo - 2 Placebo DMTS Patches<br>2 Placebo DMTS patches will be applied to the upper back and worn for 4 days (96 hours) | Drug: Placebo - 2 Placebo DMTS Patches<br>* 2 Placebo DMTS patches applied to the upper back followed 7 days later by another application of 2 Placebo DMTS patches. Each application will be worn for 4 days (96 hours)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the Neuropsychiatric Inventory - Nursing Home Version (NPI-NH) (at 7 days post-dose)application of DMTS compared with placebo | The Neuropsychiatric Inventory - Nursing Home Version (NPI-NH) is an instrument designed to record and measure the frequency and severity of agitation behaviors with a 7-day lookback period. The NPI-NH Agitation Item (C) will be administered by a certified clinician to a qualified caregiver. Based upon a positive response to the screening question, follow-up questions are read and yes/no responses are recorded. Both frequency and severity are evaluated based upon the most abnormal behavior revealed in the follow-up questions. After frequency and severity have been determined, the caregiver is asked to rate the level of disruptiveness of the behavior. | Day 1 (Pre-dose}, Day 8 (Pre-dose), Day 15 (EOS) | 
| CGI-I score at 96 hours post-dose of DMTS compared to placebo.days) of DMTS compared to placebo | The Clinical Global Impression Scale - Improvement (CGI-I) is a one item, 7-point (1 - 7) clinician-rated scale in which lower ratings indicate greater improvement. The CGI-I will be rated based on improvement of agitation symptoms and behaviors. | Day 5, Day 6, Day 7, Day 12, Day 13, Day 14 and Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Cohen-Mansfield Agitation Inventory (CMAI) score at 96 hours post application of DMTS compared with placebo | The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item clinician-administered scale systematically assessing the frequency of agitation episodes (physical agitation, non-physical agitation, verbal agitation) over the past week. Caregiver serves as the informant. The Total Score ranges from 29 to 203, with higher scores indicating more frequent episodes of agitation. Each item is rated on a 7-point scale. | Day 1 (Pre-dose), Day 5 (96-hour), Day 8 (Pre-dose), Day 12 (96-hour) | 
| • Change from baseline in Cohen-Mansfield Agitation Inventory (CMAI) score at 2 weeks post application of DMTS compared with placebo (Day 15).application of DMTS compared with placebo | The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item clinician-administered scale systematically assessing the frequency of agitation episodes (physical agitation, non-physical agitation, verbal agitation) over the past week. Caregiver serves as the informant. The Total Score ranges from 29 to 203, with higher scores indicating more frequent episodes of agitation. Each item is rated on a 7-point scale. | Day 1 (Pre-dose), Day 15 | 
| Change from baseline in the Neuropsychiatric Inventory - Nursing Home Version (NPI-NH) at 7 days post application of DMTS compared to placebo. | The NPI-NH Agitation Item (C) will be administered by a certified clinician to a qualified caregiver. Based upon a positive response to the screening question, follow-up questions are read and yes/no responses are recorded. Both frequency and severity are evaluated based upon the most abnormal behavior revealed in the follow-up questions. After the frequency and severity of has been determined, the caregiver is asked to rate the level of disruptiveness of the behavior. | Day 1 (Pre-dose), Day 8 and Day 15 | 
| • CGI-I score at 2 weeks post-dose of initial application of DMTS compared to placebo weeks post application of DMTS compared with placebo | The Clinical Global Impression Scale - Improvement (CGI-I) is a one item, 7-point (1 - 7) clinician-rated scale in which lower ratings indicate greater improvement. The CGI-I will be rated based on improvement of agitation symptoms and behaviors. | Day1 (Pre-dose), Day 15 | 
| Change from baseline in Clinical Global Impression Scale - Severity (CGI-S) score compared to placebo at specified timepoints post application of DMTS | The Clinical Global Impression Scale - Severity (CGI-S) is a one item, 7-point (1 - 7) clinician rated scale in which higher ratings indicate greater severity of agitation. The CGI-S will be rated based on severity of agitation. | Day 1 (Pre-dose), Day 5, Day 6, Day 7, Day 12, Day 13, Day 14 and Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Agitation, Dementia, DMTS