Cannabidiol Medication Intervention Trial

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.

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.

Eligibility Criteria:
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