Nabilone for Agitation in Alzheimer's Disease

(NAB-IT Trial)

Recruiting at 5 trial locations

Overseen By NAB-IT Coordinating Centre

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Sunnybrook Health Sciences Centre

Must be taking: Cognitive enhancers

Must not be taking: Antidepressants, Cannabis

Disqualifiers: Cardiovascular disease, Liver disease, Psychiatric disorders, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

112 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will look at whether nabilone is an effective treatment for agitation in Alzheimer's disease (AD) patients. Agitation is highly prevalent in patients with AD and is one of the most distressing and challenging-to-treat symptoms. Agitation is associated with faster progression to institutionalization, increased caregiver burden, poorer quality of life, and increased risk of death. In addition, current pharmacological options show only modest efficacy and elevated risks of adverse events. Therefore, identifying safer and more effective treatments for agitation in AD is a clinical and research priority. Nabilone is a synthetic cannabinoid that is Health Canada-approved to treat chemotherapy-induced nausea and vomiting. The PI's research group completed a 6-week double-blind placebo-controlled randomized cross-over pilot trial in 38 patients with moderate-to-severe AD, providing the first preliminary evidence regarding the safety and efficacy of nabilone in this population. They found that nabilone significantly improved agitation, overall neuropsychiatric symptoms, and caregiver distress. That study was limited by its sample size and questions remain regarding the efficacy of nabilone for nutrition and pain and predictors of response. However, the promising preliminary findings encourage a pivotal, practice-changing phase III trial to inform clinical practice. Participants in this study will be randomized to receive either nabilone or a placebo for 8 weeks. In addition to looking at the effectiveness of nabilone 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. Participants will also be followed for 8 weeks following completion of the study treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but if you are taking cognitive-enhancing medications, your dosage must be stable for at least 3 months before joining. Also, you should not have changed any psychotropic medications within 1 week before starting the trial.

What data supports the effectiveness of the drug nabilone for treating agitation in Alzheimer's disease?

Nabilone, a synthetic cannabinoid, is being studied for its potential to safely and effectively reduce agitation in Alzheimer's patients, with possible additional benefits for weight and pain management. Emerging evidence also suggests it may have protective effects on the brain. ^{1 2 3 4 5}

Is nabilone generally safe for human use?

Nabilone has been studied for its safety in treating agitation in Alzheimer's disease and severe nausea from cancer chemotherapy. While it can be effective, it often causes side effects like drowsiness, dizziness, and vertigo in 60-70% of patients, and more serious effects like low blood pressure and vision problems may occur, leading to discontinuation in some cases. ^{1 2 6 7 8}

How does the drug nabilone differ from other treatments for agitation in Alzheimer's disease?

Nabilone is unique because it is a synthetic cannabinoid that may offer a safer and more effective treatment for agitation in Alzheimer's disease, with potential benefits for weight and pain management, and possible neuroprotective effects, unlike traditional medications whose safety profiles are often questionable. ^{1 2 8 9 10}

Research Team

Krista L. Lanctot, PhD

Principal Investigator

Sunnybrook Research Institute

Giovanni Marotta, MD

Principal Investigator

Sunnybrook Health Sciences Centre

Eligibility Criteria

This trial is for men and women over 55 with Alzheimer's who experience significant agitation. Women must be post-menopausal, and participants should have a stable dose of cognitive-enhancing meds for at least 3 months. They need a caregiver who speaks English well. People using cannabis recently, on certain drugs, or with uncontrolled heart disease or liver issues can't join.

Inclusion Criteria

I experience severe restlessness as defined by health professionals.

My medication for memory or thinking problems has been the same for the last 3 months.

I am a man or a post-menopausal woman aged 55 or older.

Exclusion Criteria

You have used marijuana or other cannabis products for fun in the 3 months before the study starts.

I am not allergic to cannabis or its products and do not have drug interactions.

You currently have symptoms that meet the criteria for a major depressive episode according to the DSM 5.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive either nabilone or a placebo for 8 weeks to assess the effectiveness of nabilone in treating agitation and other outcomes in Alzheimer's disease patients.

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

8 weeks

Treatment Details

Interventions

• Nabilone
• Placebo

Trial Overview The study tests if nabilone helps reduce agitation in Alzheimer's patients compared to a placebo over an 8-week period. It also examines its effects on neuropsychiatric symptoms, caregiver stress, cognition, nutrition, and pain. Participants are randomly assigned to either the drug or placebo group.

Participant Groups

Group I: Nabilone Arm Experimental Treatment 1 Intervention

Participants randomized to the nabilone arm will be titrated up to a maximum dose of 2 mg/day.

Group II: Placebo Arm Placebo Group 1 Intervention

Participants randomized to the placebo arm will receive placebo capsules.

Nabilone is already approved in United States, Canada, United Kingdom for the following indications:

Approved in United States as Cesamet for:

• Chemotherapy-induced nausea and vomiting

Approved in Canada as Cesamet for:

• Chemotherapy-induced nausea and vomiting

Approved in United Kingdom as Cesamet for:

• Chemotherapy-induced nausea and vomiting

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Alzheimer's Drug Discovery Foundation

Collaborator

Trials

22

Recruited

3,100+

Weston Brain Institute

Collaborator

Trials

13

Recruited

990+

Findings from Research

In a 14-week study involving 39 patients with moderate-to-severe Alzheimer's disease, nabilone significantly reduced agitation compared to placebo, as measured by the Cohen Mansfield Agitation Inventory.

While nabilone showed promise in reducing agitation and caregiver distress, it also caused more sedation, indicating that monitoring for sedation and cognitive effects is important when using this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer's Disease. Herrmann, N., Ruthirakuhan, M., Gallagher, D., et al.[2020]

A clinical trial is underway to evaluate nabilone, a synthetic cannabinoid, for treating agitation in patients with moderate-to-severe Alzheimer's disease, comparing its effects to a placebo over 6 weeks.

The study aims to assess not only the efficacy in reducing agitation but also the safety and potential benefits on pain, weight, and overall quality of life, which could help reduce caregiver stress and healthcare costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigating the safety and efficacy of nabilone for the treatment of agitation in patients with moderate-to-severe Alzheimer's disease: Study protocol for a cross-over randomized controlled trial. Ruthirakuhan, MT., Herrmann, N., Gallagher, D., et al.[2022]

In two 12-week studies involving a total of 703 patients with agitation in Alzheimer's dementia, brexpiprazole at a dose of 2 mg/day showed significant improvement in agitation symptoms compared to placebo, indicating its efficacy in this patient population.

Brexpiprazole was generally well tolerated, with most treatment-emergent adverse events being mild to moderate, although headaches and insomnia were reported more frequently than with placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled Trials. Grossberg, GT., Kohegyi, E., Mergel, V., et al.[2021]

In a study involving 149 participants with moderate-to-severe Alzheimer's disease, memantine did not show a significant improvement in clinically significant agitation compared to placebo after 6 weeks, indicating it may not be effective for this symptom.

However, memantine did demonstrate a positive effect on cognitive function and showed some benefits in reducing neuropsychiatric symptoms, suggesting it may still have a role in managing other aspects of Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of memantine for agitation in Alzheimer's dementia: a randomised double-blind placebo controlled trial. Fox, C., Crugel, M., Maidment, I., et al.[2022]

In a pilot study involving 26 nursing home residents with Alzheimer's disease, buspirone (15 mg) was found to reduce agitation and anxiety more effectively than haloperidol (1.5 mg) over a 10-week period.

While the study lacked a placebo group, the results indicate that buspirone may be a promising option for managing agitation in Alzheimer's patients, warranting further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buspirone vs. Haloperidol: A Double-Blind Trial for Agitation in a Nursing Home Population With Alzheimer's Disease. Cantillon, M., Brunswick, R., Molina, D., et al.[2019]

Citalopram has shown promising efficacy in treating agitation in Alzheimer's disease dementia, potentially benefiting from a class effect seen in selective serotonin reuptake inhibitors, but concerns about its cardiac side effects have limited its use.

The article reviews safety and efficacy data for both citalopram and escitalopram, providing practical recommendations and risk mitigation strategies to enhance their use in clinical practice for managing agitation in dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

When and How to Treat Agitation in Alzheimer's Disease Dementia With Citalopram and Escitalopram. Aga, VM.[2022]

Nabilone, an orally active cannabinoid, significantly reduces nausea and vomiting in 50 to 70% of patients experiencing severe gastrointestinal toxicity from chemotherapy, especially when conventional treatments fail.

While nabilone is more effective and preferred over prochlorperazine for symptom control, it has a high incidence of side effects, including drowsiness and dizziness, affecting 60 to 70% of patients, though serious side effects leading to discontinuation are rare.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nabilone. A preliminary review of its pharmacological properties and therapeutic use. Ward, A., Holmes, B.[2018]

In a 14-week study involving 38 patients with Alzheimer's disease, the cannabinoid nabilone was associated with reduced agitation, particularly in patients with lower levels of the inflammatory marker TNF-α.

The study suggests that oxidative stress and neuroinflammation are linked to agitation severity in Alzheimer's patients, and nabilone may exert anti-inflammatory effects that contribute to its efficacy in reducing agitation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Agitation, Oxidative Stress, and Cytokines in Alzheimer Disease: Biomarker Analyses From a Clinical Trial With Nabilone for Agitation. Ruthirakuhan, M., Herrmann, N., Andreazza, AC., et al.[2020]

Citalopram was found to be effective in reducing agitation in Alzheimer's disease, showing superior results compared to placebo in both primary response measures after 9 weeks of treatment.

The study highlighted that a longer treatment duration of at least 9 weeks is necessary to observe the full benefits of citalopram, as many patients showed a delayed response, particularly in the later stages of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Time to Response to Citalopram Treatment for Agitation in Alzheimer Disease. Weintraub, D., Drye, LT., Porsteinsson, AP., et al.[2022]

The CitAD study, involving 200 individuals with Alzheimer's disease and significant agitation, evaluated the efficacy of citalopram compared to a placebo, aiming to provide a potential treatment option for this common neuropsychiatric symptom.

The study's design, which included structured psychosocial therapy for caregivers and robust outcome measures, highlights important considerations for future trials assessing psychotropic medications for agitation in Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Citalopram for agitation in Alzheimer's disease: design and methods. Drye, LT., Ismail, Z., Porsteinsson, AP., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Randomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer's Disease. [2020]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Investigating the safety and efficacy of nabilone for the treatment of agitation in patients with moderate-to-severe Alzheimer's disease: Study protocol for a cross-over randomized controlled trial. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled Trials. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Efficacy of memantine for agitation in Alzheimer's dementia: a randomised double-blind placebo controlled trial. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Buspirone vs. Haloperidol: A Double-Blind Trial for Agitation in a Nursing Home Population With Alzheimer's Disease. [2019]

6. England pubmed.ncbi.nlm.nih.gov

When and How to Treat Agitation in Alzheimer's Disease Dementia With Citalopram and Escitalopram. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Nabilone. A preliminary review of its pharmacological properties and therapeutic use. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Agitation, Oxidative Stress, and Cytokines in Alzheimer Disease: Biomarker Analyses From a Clinical Trial With Nabilone for Agitation. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Time to Response to Citalopram Treatment for Agitation in Alzheimer Disease. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Citalopram for agitation in Alzheimer's disease: design and methods. [2022]