| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Alzheimer's disease patients with BPSD |
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| E.1.1.1 | Medical condition in easily understood language |
| Alzheimer's disease patients with behavioural and psychological symptoms e.g. anxiety, agitation, hallucinations and delusions |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Behavioral Disciplines and Activities [F04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
| E.1.2 | System Organ Class | 100000004852 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
(i)Acceptability: To investigate the acceptability of the randomisation procedure and delivery of the intervention (CBD or placebo in capsule form) to the AD patients and carers (recruitment rates).
(ii)Retention: To measure the study retention rate (follow-up rates).
(iii)Compliance: To assess compliance with treatment (adherence).
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| E.2.2 | Secondary objectives of the trial |
(i)To measure key outcome domains for patients including clinical measures -BPSD, cognition, quality of life, smell functioning, daily functioning and carer’s distress
(ii)To assess the safety (adverse events) and tolerability (side-effects) of CBD treatment
(iii)To describe the variance and distribution of quantitative outcomes to pilot effect sizes and inform the design and sample size calculation in the future large-scale RCT
iv)To investigate the acceptability of the questionnaires used to measure the key outcome domains (percentage of completion rates)
Mechanistic sub-study: We aim to investigate the mechanistic basis of any CBD effect observed during the RCT using functional brain imaging and spectroscopy.
Qualitative interviews: The aim of the qualitative interviews will be to explore participants’ experiences of taking part in the trial including what
encouraged them to take part, their views on the intervention and how they are finding the trial in general. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Mechanistic sub-study (included as addendum to main protocol, version 1.0)
Aims: We aim to investigate the mechanistic basis of any CBD effect observed during the RCT using functional brain imaging.
Methods: Nested within the main trial, we will carry out a mechanistic sub-study using magnetic resonance imaging (MRI). Neuroimaging (task based and resting state fMRI; spectroscopy and structural MRI) data will be acquired using well-established protocols on the the 3 Tesla scanner (GE SIGNA HDx 3.0T MR scanner system) at the NIHR King's Wellcome CRF or Centre for neuroimaging Sciences at Denmark Hill.
Neuroimaging will be done pre-treatment (baseline visit) and then after 6 weeks of treatment (follow-up visit 3) and will be offered to all participants in the trial. Each patient will be scanned over a 60-minute period.
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| E.3 | Principal inclusion criteria |
(1) Age 55 and above from both genders;
(2) Living within the SLAM/South London region;
(3) Diagnosis of AD according to the criteria of National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA);
(4) Clinical Dementia Rating (CDR) score between 0.5-2;
(5) BPSD lasting for at least 2 weeks with total score on Neuropsychiatric Inventory (NPI) ≥4 and at least 1 item with moderate frequency or severity on one of the domains of anxiety, agitation, hallucinations or delusions;
(6) If treated with cholinesterase inhibitors (donepezil, rivastigmine or galantamine) and/or memantine, dosage must have been stable for at least 1 month; If ChEIs and/or memantine has been discontinued, they may enrol 1 month following discontinuation.
(7) Ability to participate in study evaluation and ingest oral medication.
(8) Reliable informant/caregiver.
(8) Written informed consent from participant or their legally authorised representative.
Eligibility criteria for caregivers:
(1) See the patient for an average of 6 hours per week
(2) Willing to attend all study visits with the participant and participate in weekly calls
(3) Able to answer questions about the participant’s behavioural and psychological symptoms, daily activities, quality of life, memory, health and any side effects that they may be experiencing from the study medication
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| E.4 | Principal exclusion criteria |
(1) Presence or history of other psychiatric or neurological disorders (e.g. psychotic disorders, schizophrenia, major depressive illness including suicidal ideation, stroke, epilepsy) or severe intercurrent physical illness that could interfere with the conduct of the study.
(2) Participants who answer "yes" on the C-SSRS Suicidal Ideation Item 4 or Item 5 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan, or Active Suicidal Ideation with Specific Plan and Intent) and whose most recent episode meeting the criteria for C-SSRS Item 4 or Item 5 occurred within the last 6 months, OR Participants who answer "yes" on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) and whose most recent episode meeting the criteria for any of these 5 C-SSRS Suicidal Behavior iItems occurred within the last 2 years, OR Participants who, in the opinion of the investigator, present a serious risk of suicide.
(3) Changes in dosage of antidepressants within 4 weeks before randomization and during study, and changes in dosage antipsychotics or benzodiazepines within 2 weeks prior to randomization and during study.
(4) Use of co-medication that has a clinically relevant interaction with the CYP2C19 or CYP3A classes of liver enzymes will not be permitted from two weeks before inclusion until the end of the study. Examples of co-medication that will be not allowed will include CYP3A4 inhibitors (such as itraconazole, ketoconazole, posaconazole, fluconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, telaprevir, boceprevir, imatinib, ticagrelor, voriconazole), CYP3A4 inducers (such as grapefruit juice, carbamazepine, efavirenz, nevirapin, etravirin) and CYP2C19 inhibitors (such as moclobemine, fluvoxamine, chloramphenicol, fluoxetine).
(5) If the patient has participated in other interventional clinical studies within 30 days of baseline.
(6) Female patients who are pregnant or lactating
(7) Female patients of childbearing potential* who are not willing to use a highly effective method of contraception** for the duration of the trial (from the date of consent until entire study duration, i.e., until the 4 weeks follow up visit post-treatment) to prevent pregnancy or abstain from heterosexual activity. *Females of childbearing potential are females who have experienced menarche and are not surgically sterilised (e.g. hysterectomy or bilateral salpingectomy) or postmenopausal (defined as at least 1 year since last regular menstrual period).
** Highly effective methods of birth control are those with a failure rate of < 1% per year when employed consistently and correctly, e.g. • combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: o oral o intravaginal o transdermal • progestogen-only hormonal contraception associated with inhibition of ovulation 1: o oral o injectable o implantable 2 • intrauterine device (IUD) • intrauterine hormone-releasing system ( IUS) • vasectomised partner
Sexual abstinence is considered to be highly effective method only if defined as refraining from heterosexual activity from the date of consent until entire study duration, i.e., until the 4 weeks follow up visit post-treatment. The reliability of this method should be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.
(8) Known hypersensitivity to CBD gelatine or micro-crystalline cellulose.
(9) Mechanistic sub-study only: Patients who have any contraindications to MRI, including: pacemakers, metallic foreign body in the eye, aneurysm clip in their brain, severe claustrophobia where patients would not be able to tolerate the scan etc
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Recruitment: number of participants recruited, consented and randomised in 9 months
2. Percentage of patients compliant* with treatment by the end of 6-weeks
3. Retention rate (measured by drop-out) by the end of 6-week treatment and missing data
*Defined as at least 60% of the dose taken, measured by pill count |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After the last visit of the final patient is complete |
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| E.5.2 | Secondary end point(s) |
Change in mean score at week 6 compared to baseline (pre-treatment) and 95% confidence intervals for the following measures:
NeuroPsychiatry Inventory (NPI-C)
Standardised Mini-Mental State Examination (SMMSE)
Addenbrooke's Cognitive Examination-III (ACE-III)
Hopkins Verbal Learning Test (HVLT)
Cohen Mansfield Agitation Inventory (CMAI)
Clinical Global Impression of Change (CGIC)
DEMQOL and DEMQOL-Proxy
Bristol Activities of Daily Living Scale (BADLS)
Smell Functioning Test (UPSIT)
Tolerability: Assessed by self-report of side-effects, medication discontinuation and the UKU side-effect rating scale for psychotropic drugs
Safety parameters: Bloods Haematology (Haemoglobin, Red blood cell count, Platelet count, white blood cell count and differential count), Clinical chemistry (Sodium, Potassium, Creatinine, Urea); Glucose; Liver function test (Total bilirubin, Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline phosphatase); cholesterol (total, LDL, HDL); T3, T4 and Thyoridthyroid stimulating hormone; Vital signs: Heart rate and Blood pressure; Physical examination; Electrocardiogram (ECG)- 12 lead ECG
Mechanistic sub-study: 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)
Qualitative interviews: The aim of the qualitative interviews will be to explore participants’ experiences of taking part in the trial including what
encouraged them to take part, their views on the intervention and how they are finding the trial in general. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After the last visit of the final patient is complete |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial will be defined as database lock.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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