Cannabidiol Medication Intervention Trial

Phase 2

Recruiting

• Conditions: Alzheimer Disease
• Interventions: Other: Placebo; Drug: CBD

• Registration Number: NCT06014424
• Lead Sponsor: Sunnybrook Health Sciences Centre

Brief Summary

CALM-IT is a Randomized, double-blind, placebo-controlled cross-over clinical trial. Safety and efficacy of cannabidiol (CBD) capsules assessed for managing agitation in patients with AD and to identify novel biomarkers of agitation severity and treatment response.

Detailed Description

This study will look at whether CBD is an effective treatment for agitation in Alzheimer's disease (AD). This naturally derived CBD is highly pure (99%) and made by a manufacturer who meets Health Canada guidelines 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 CBD 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 CBD 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.

Study Timeline

• Study First Submitted: 2023-07-24
• Study First Submitted QC: 2023-08-22
• Study First Posted: 2023-08-28
• Study Start: 2023-09-27
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-23
• Last Update Posted: 2025-04-27
• Primary Completion: 2026-12-29
• Study Completion: 2026-12-29

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

1. 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
2. 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
3. sMMSE ≤24
4. Presence of clinically significant agitation based on the IPA definition at both screening and baseline
5. If treated with cognitive-enhancing medications (cholinesterase inhibitors and/or memantine), dosage must be stable for at least 3 months prior to study randomization
6. 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
7. 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

1. 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
2. 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. Current substance dependence (excluding caffeine and nicotine)

12. Clinically significant delusions and/or hallucinations (e.g. NPI-NH delusion/hallucinations subscore ≥4 or judgement of QI)

13. Reported use of marijuana or cannabinoid-based medications, products or supplements (botanical or synthetic) within 1 week prior to randomization

14. Systolic blood pressure (SBP) < 90 mmHg or > 150 mmHg or diastolic blood pressure (DBP) < 50mmHg or > 105 mmHg at screening or baseline (prior to randomization) or a postural drop in SBP ≥ 20 mmHg or DBP ≥ 10 mmHg at screening

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participants randomized to the placebo will be titrated up to a maximum dose of 800 mg/day
CBD	CBD	Participants randomized to the CBD arm will be titrated up to a maximum dose of 800 mg/day

Primary Outcome Measures

Name	Time	Method
Agitation - Cohen-Mansfield Agitation Inventory (CMAI)	Baseline (0 Weeks) to 22 Weeks	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.

Secondary Outcome Measures

Name	Time	Method
Behavior - Neuropsychiatric Inventory - Clinician Scale (NPI-C Agitation/NPI-NH)	Baseline (0 Weeks) to 22 Weeks	NPI-C agitation is a widely used assessment of behaviour disturbances in dementia, including: apathy agitation, delusions, hallucinations, depression, euphoria, aberrant motor behaviour, irritability, disinhibition, anxiety, sleeping, and eating. NPI-NH is a caregiver-rated scale that is widely used to assess behavioral disturbances in dementia as well as caregiver distress. These behaviours include: delusions, hallucinations, agitation, aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, sleep, appetite and eating disorders, and aberrant vocalizations. 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.
Cognition - Standardized Mini-Mental State Examination (sMMSE)	Baseline (0 Weeks) to 22 Weeks	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.
Weight	Baseline (0 Weeks) to 22 Weeks	Weight will be collected in kilograms. A change of 7% in weight will be considered clinically significant change.
Nutritional Status - Mini Nutritional Assessment - Short Form (MNA-SF)	Baseline (0 Weeks) to 22 Weeks	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.
Pain - Pain Assessment Checklist for Seniors with Limited Ability to Communicate - II (PACSLAC-II)	Baseline (0 Weeks) to 22 Weeks	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.
Global Change - Alzheimer's Disease Cooperative Study - Clinical Global Impression of Severity/Change (ADCS-CGIS/C)	Baseline (0 Weeks) to 22 Weeks	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.

Trial Locations

Locations (3)

Sunnybrook Health Sciences Centre; 🇨🇦 Toronto, Ontario, Canada

Ontario Shores Centre for Mental Health Sciences; 🇨🇦 Whitby, Ontario, Canada

University of Calgary; 🇨🇦 Calgary, Alberta, Canada