Cannabinoid Liquid Medication Intervention Trial

Study Overview
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Brief Summary
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CALM-IT is a Randomized, double-blind, placebo-controlled cross-over clinical trial. Safety and efficacy of JZP541 assessed for managing agitation in patients with AD and to identify novel biomarkers of agitation severity and treatment response.

Detailed Description
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This study will look at whether JZP541 is an effective treatment for agitation in Alzheimer's disease (AD). JZP541 is a botanical cannabinoid drug product containing cannabidiol (CBD), cannabichrome (CBC) and delta-9-tetrahydrocannabinol (THC), amongst other cannabinoid and noncannabinoid plant-derived components. Cannabis products are legal for purchase in Canada. Agitation is common in AD and is known to correlate with physical health problems such as falls and weight loss, AD progression, and caregiver burden. Current treatments for agitation in AD are not beneficial for everyone and there are concerns regarding their safety. Treating agitation is important in improving the quality of life of AD patients and their families and there is a need to identify safer and more effective treatments for agitation in AD. The structure of this trial is called a cross-over study. Participants will be randomized to receive either JZP541 or placebo during the first of two treatment phases. They will then cross-over to the opposite treatment during the second treatment phase. Participants will be on the study treatment for a total of 19 weeks and then will be followed for 4 more weeks after finishing the study treatment. There will be 12 study visits approximately every 2 weeks and 8 telephone visits every week during the study. In addition to looking at the effectiveness of JZP541 in treating agitation, the researchers will also look at whether it is beneficial for other relevant outcomes for patients with AD including overall neuropsychiatric symptoms, caregiver distress, cognition, nutritional status, and pain.

Official Title
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Cannabinoid Liquid Medication Intervention Trial (CALM-IT)

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: JZP541
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females ≥55 years of age; female must be post-menopausal or must agree to comply with contraception requirements. Males should also abide by contraceptive requirements when the partner is a woman of childbearing potential. Acceptable methods of contraception include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, which may be oral, intravaginal, or transdermal; progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injectable, or implantable; intrauterine device or intrauterine hormone-releasing system; vasectomy of a female subject's male partner (with medical assessment and confirmation of vasectomy surgical success); bilateral tubal occlusion Diagnostic and Statistical Manual of Mental Disorders-5 (DSM 5) criteria for Major Neurocognitive Disorder due to possible AD. Patients with Major Neurocognitive Disorder due to multiple etiologies (AD and vascular) will be included sMMSE ≤24 Presence of clinically significant agitation based on the IPA definition at both screening and baseline If treated with cognitive-enhancing medications (cholinesterase inhibitors and/or memantine), dosage must be stable for at least 3 months prior to study randomization Availability of a primary caregiver to accompany the participant to study visits and to participate in the study. The primary caregiver must be sufficiently proficient in English to complete the required study assessments, as per investigator judgement and should spend at least 10 hours a week with the participant Willing and able to provide informed consent and/or have a Substitute Decision Maker (SDM) provide informed consent on behalf of the participant Exclusion Criteria: Change in psychotropic medications less than the duration of 5 half-lives of the medication in question prior to screening (e.g., concomitant antidepressants or atypical antipsychotics) and any changes during study participation Administration of strong inducers of CYP3A4 ≤ 14 days prior to first doses of study intervention or have ongoing requirements for these medications 3) Use of anticonvulsant medications 4) Contraindications to CBs, e.g. allergies to cannabis and cannabis products, potential clinically important drug-drug interactions 5) Any type of arterial vascular disease, cerebrovascular disease and current uncontrolled cardiovascular disease (e.g. uncontrolled hypertension, ischemic heart disease, arrhythmia and severe heart failure), as per investigator assessment 6) Patients with Cardiovascular Accident in the 3 months prior to Screening (V1) 7) Impaired hepatic function, as reflected by serum alanine aminotransferase or aspartate aminotransferase > 2 × upper limit of normal (ULN), or total bilirubin > 1.5 × ULN; the Investigator may decide to repeat the assessment to confirm criterion prior to screen failing the participant 8) Presence of clinically significant impaired renal function at screening, as evidenced by an estimated creatinine clearance < 30 mL/min/1.73 m2 (as calculated by the glomerular filtration rate using the Modification of Diet in Renal Disease study equation) 9) Presence or history of other psychiatric disorders or neurological conditions (e.g. psychotic disorders, schizophrenia, stroke, epilepsy) and known or suspected psychotic disorder in a first degree relative 10) Participants currently meeting DSM 5 criteria for Major Depressive Episode 11) History of suicidal behavior or suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) 12) Current substance dependence (excluding caffeine and nicotine) 13) Clinically significant delusions and/or hallucinations (NPI-C delusion/hallucinations subscore ≥4) 14) Reported use of marijuana or cannabinoid-based medications, products or supplements (botanical or synthetic) within 1 week prior to randomization 15) Systolic blood pressure (SBP) < 90 mmHg or > 150 mmHg or diastolic blood pressure (DBP) < 50 mmHg or > 105 mmHg at screening or baseline (prior to randomization) or a postural drop in SBP ≥ 20 mmHg or DBP ≥ 10 mmHg at screening 16) QT Interval Corrected Using Fridericia's Formula > 450 ms (confirmed by 2 consecutive electrocardiograms (ECGs) or a history of additional risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)

Ages Eligible for Study
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Minimum Age: 55 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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: JZP541<br>Participants randomized to the JZP541 arm will be titrated up to a maximum dose of 26 mL/day | Drug: JZP541<br>* Participants in this arm will receive ZP541 for 8 weeks during the first treatment period. They will then receive a two-week single-blind placebo washout before moving into the second 8-week treatment period, during which they will receive the opposite study treatment than the one given in the first treatment period.<br>|
| Experimental: Placebo<br>Participants randomized to the placebo will be titrated up to a maximum dose of 26 mL/day | Other: Placebo<br>* Participants in this arm will receive placebo for 8 weeks during the first treatment period. They will then receive a two-week single-blind placebo washout before moving into the second 8-week treatment period, during which they will receive the opposite study treatment than the one given in the first treatment period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Agitation - Cohen-Mansfield Agitation Inventory (CMAI) | A 29-point scale that measures agitation in two dimensions, verbal and physical, each of which having two poles, aggressive and on-aggressive. Scores range from 29-203 points, with a higher score indicating a worse outcome. | Baseline (0 Weeks) to 22 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Behaviour - Neuropsychiatric Inventory - Clinician Scale (NPI-C) | A widely used assessment of behaviour disturbances in dementia, including: apathy agitation, delusions, hallucinations, depression, euphoria, abeerant motor behaviour, irritability, disinhibition, anxiety, sleeping, and eating. The frequency and severity of these symptoms are judged on a 4-point and 3-point scale, respectively. Scores range from 0-144 points, with a higher score indicating a worse outcome. | Baseline (0 Weeks) to 22 Weeks | 
| Cognition - Standardized Mini-Mental State Examination (sMMSE) | Measures global cognition, and assesses orientation to time and place, immediate recall, short-term verbal memory, calculation, language, and construct ability. Scores range from 0-30 points, with a lower score indicating a worse outcome. | Baseline (0 Weeks) to 22 Weeks | 
| Weight | Weight will be collected in kilograms. A change of 7% in weight will be considered clinically significant change. | Baseline (0 Weeks) to 22 Weeks | 
| Nutritional Status - Mini Nutritional Assessment - Short Form (MNA-SF) | A structured interview consisting of 6 items that categorizes patients as malnourished, at risk of malnutrition, or of normal nutritional status. Scores range from 0-14 points, with a lower score indicating a worse outcome. | Baseline (0 Weeks) to 22 Weeks | 
| Pain - Pain Assessment Checklist for Seniors with Limited Ability to Communicate - II (PACSLAC-II) | A 31-item observer-rated scale assessing facial expressions, activity/body movements, social/personality/mood indicators and mental status changes. Scores range form 0-31 points, with a higher score indicating a worse outcome. | Baseline (0 Weeks) to 22 Weeks | 
| Global Change - Alzheimer's Disease Cooperative Study - Clinical Global Impression of Severity/Change (ADCS-CGIS/C) | A commonly-used clinician-rated scale that quantifies disease severity and clinical change (worsening, no change, or improvement), based on information regarding the patient's medical history, cognition, behaviour, and function. Scores range from 1-7, with a lower score indicating a worse outcome. | Baseline (0 Weeks) to 22 Weeks |