NAME OF RESEARCHERS
Dr Latha Velayudhan / Dr Sagnik Bhattacharyya
NAME OF SUPERVISOR
Not applicable
PROJECT TITLE
CANnabidiol for Behavioural Symptoms in Alzheimer’s Disease (CANBiS-AD)
CLINICAL ACADEMIC GROUP: Mental health for Older adults (MHOA) and Dementia CAG
START & FINISH DATES
Initially awarded on 1st June 2019, with an expected start date in April 2020. However, due to the pandemic all patient-facing research activity (with some exceptions) were paused from March 2020. Hence, despite obtaining ethical and regulatory approval by April 2020, we were finally given the go-ahead to start the study from May 2021. The end date of the award was requested and extended to 30th June 2022.
PROJECT DESCRIPTION
Behavioral and Psychological Symptoms of Dementia (BPSD) in people with Alzheimer’s disease (AD) is particularly distressing to patients and carers. There are currently no licensed medications for BPSD, and the current available treatment have limited benefits and greater risk for side effects. There is therefore a considerable unmet clinical need for interventions that are safe, well-tolerated and effective for treating BPSD in AD. A growing body of evidence suggests that cannabidiol (CBD), a non-addictive substance present in cannabis, has antianxiety and antipsychotic properties and is safe and well-tolerated in different patient groups including in the elderly. We conducted a pilot trial to obtain preliminary evidence and to test the feasibility of cannabidiol (CBD) as an adjunct to existing treatment (treatment as usual; TAU) to reduce BPSD in patients with AD (KHP R&D Challenge funds, 2019-2022).
Another critical aspect of evidence that would be important in supporting future clinical development work with CBD in AD and BPSD relates to understanding its potential mechanism of action. We sought PRT funding to augment the feasibility clinical trial of CBD by also examining the feasibility of investigating the mechanistic basis of any CBD effect observed during the RCT using functional brain imaging and collect some pilot data.
To investigate the mechanism of action of CBD, we planned to examine the within-subject change in brain function and connectivity [as measured using task-based (verbal learning) and resting state fMRI] following treatment between the two treatment conditions (CBD and placebo). Neuroimaging was done pre-treatment and then after 6 weeks of treatment.
PROGRESS IN PAST YEAR
We conducted a phase 2a double-blind, parallel group, placebo-controlled pragmatic randomized controlled feasibility trial (EudraCT Number - 2019-002106-52). Ethics approval was obtained from the National Health Service Health Research Authority and Cambridge East Research Ethics Committee (20/EE/0014) and the Medicines and Healthcare products Regulatory Agency.
We faced a number of challenges due to the multiple waves of the COVID-19 pandemic and risk to potential trial participants, who were already vulnerable to covid because of their age and co-morbid health conditions. As a result, trial start was delayed, and we were finally allowed to commence recruitment in May 2021. Any study using investigational medicinal product (IMP) such as the one that we carried out has to comply with a number of regulatory requirements in order to ensure that they are fit for human trial. As this study was the first of its kind using this product, the initial shelf-life certification of the CBD formulation used in the trial was based on shelf life of the drug substance (CBD) that went into making the CBD capsules with additional requirement for real life testing of the substance in parallel with the study. This protocol was approved by the UK drugs regulator (MHRA). The delayed start to the trial (originally anticipated around April 2020) meant that we were approaching shelf-life (which was approved to be 18 months by the UK regulator MHRA, UK) expiry of study drug within a few months of recruitment initiation. Given the ongoing pandemic-related restrictions, approval of extension to shelf-life by the regulator (MHRA), re-labelling of study drug (IMP), shipment of IMP to study site etc took longer than would have happened otherwise. As a result, the study had to be paused for about 8 weeks (Dec 2021 to Jan 2022) while all these activities to comply with regulatory requirements were completed. Further, this also meant that the shelf-life extension that was allowable by the regulator (MHRA) as per original protocol was also limited in light of expiry of the CBD drug substance (a 3 -year shelf of the drug substance) that was used to formulate the CBD capsules. Hence, on that basis, the extended shelf-life of the CBD capsule used in the study was approved by MHRA as 30th April 2022. This meant that the final recruitment date for the study was 18th March 2022 to ensure that the patient recruited on that date completed the trial by the 30th of April 2022.
Despite the challenges posed by the COVID-19 pandemic, we were able to screen 22 participants and randomise 15 patients over 8 months from one site. There were additional patients who had signed up for the trial but then developed covid infection during the spring of 2022, following the relaxation of safe distancing and masking rules. As a result, a further patients could not enter into the trial despite being interested. There was a lot of interest in taking part in the trial in general, and those took part experienced no major side effects, and none of them dropped out of the trial indicating that they found the study drug acceptable.
Neuroimaging (verbal learning, resting state fMRI and structural MRI) data was acquired using well-established protocols on the the 3 Tesla scanner (GE SIGNA HDx 3.0T MR scanner system) at the NIHR/ Wellcome BRC clinical research facility (where the RCT was conducted) at the Denmark Hill campus.
What this research has shown.
Of the participants randomised, there was very good adherence to treatment, no major side effects and no withdrawals. CBD was acceptable, safe and tolerable for people with AD with BPSD. Symptom improvement was observed for BPSD, daily activities, cognition and quality of life.
We found that it was challenging to scan (MRI) people with AD and behaviour problems as they tended to get more anxious, restless and agitated inside the closed and dark scanner environment. Further, separation from the carer (who could not be inside the scanner area) made it particularly difficult for many of the participants. There was a lot of movement which impaired the quality of scans. The COVID-19 pandemic also limited people who would have volunteered and social distancing restrictions limited presence of family or researcher to be able to re-assure those when in scanner in some cases.
Of the 15 patients who were randomised to treatment, 8 participants refused to take part in scans, 2 were not eligible, and of the remaining 5, we managed to get 8 MRI scans, 5 at baseline and 3 at follow-up.
Implications
Although, the number of scans that we were able to acquire was insufficient to generate statistically robust evidence, it has given us invaluable information for future studies. Firstly, it has demonstrated the feasibility of acquiring functional MRI scan data in AD patients with BPSD in the context of a clinical trial (which only a limited number of studies have done to the best of our knowledge) despite the additional challenges posed by the pandemic. It has also highlighted which particular scanning sequences to focus on, so as to generate valuable mechanistic information and has also generated pilot data for a future study. We are in the process of applying for funding for larger studies to test efficacy of CBD for each of the behavioural symptoms of interest in AD (such as psychosis; anxiety/agitation). These applications would include mechanistic neuroimaging sub-studies and the PRT-funded project has generated pilot data that would support these applications. In particular, we have already applied (outline) to the NIHR Efficacy and Mechanism evaluation scheme for the indication of psychosis in people with AD to carry out a fully powered efficacy trial and a mechanistic sub-study using CBD as the intervention. If shortlisted the full application will include both pilot clinical trial and neuroimaging data obtained using PRT support. We are also preparing for additional funding applications in response to specific funding calls from other funders such as the NIH, USA. Support from PRT and the original trial funder means that we are uniquely placed in terms of having supportive pilot and feasibility data for an intervention (CBD) of considerable interest to many funders worldwide for an unmet treatment need.
PUBLICATIONS & CONFERENCES ATTENDED:
Cannabidiol for neuropsychiatric symptoms in Alzheimer’s dementia.
Latha Velayudhan, Marta Dugonjic, Sara Pisani, Lucy Harborow, Dag Aarsland, Sagnik Bhattacharyya. Alzheimer's Association International Conference, July 2022, San Diego.
Latha Velayudhan, Marta Dugonjic, Sara Pisani, Lucy Harborow, Dag Aarsland, Sagnik Bhattacharyya. Cannabidiol for behaviour symptoms in Alzheimer’s disease (CANBiS-AD): A randomised, double-blind, placebo-controlled trial. Under preparation for submission to publication.