Clinical Trials Register

Summary
EudraCT Number:	2020-001056-17
Sponsor's Protocol Code Number:	3606
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2020-06-24
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2020-001056-17

A.3

Full title of the trial

A randomised feasibility trial investigating Sativex® for the treatment of the Agitation & Aggression (A/A) in Alzheimer’s Dementia.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A randomised feasibility trial investigating Sativex® for the treatment of the Agitation & Aggression (A/A) in Alzheimer’s Dementia

A.3.2

Name or abbreviated title of the trial where available

STAND (Sativex® for the Treatment of AgitatioN in Dementia)

A.4.1

Sponsor's protocol code number

3606

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Kings's College London
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Alzheimer's Research UK
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Kings College London
B.5.2	Functional name of contact point	Chris Albertyn
B.5.3	Address:
B.5.3.1	Street Address	Institute of Psychiatry , Psychology & Neuroscience (loPPN) , 16 De Crespigny Park
B.5.3.2	Town/ city	LONDON
B.5.3.3	Post code	SE5 8AF
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+4402078480548
B.5.6	E-mail	chris.albertyn@kcl.ac.uk
B.Sponsor: 2
B.1.1	Name of Sponsor	South London and Maudsley NHS Foundation Trust
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Alzheimer's Research UK
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	King's College London
B.5.2	Functional name of contact point	Chris Albertyn
B.5.3	Address:
B.5.3.1	Street Address	IOPPN, 16 De Crespigny Park,
B.5.3.2	Town/ city	London
B.5.3.3	Post code	SE58AF
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+442088480548
B.5.6	E-mail	chris.albertyn@kcl.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Sativex Oromucosal Spray
D.2.1.1.2	Name of the Marketing Authorisation holder	GW Pharma Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Sativex Oromucosal Spray
D.3.4	Pharmaceutical form	Oromucosal spray
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oromucosal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DELTA-9-TETRAHYDROCANNABINOL
D.3.9.1	CAS number	1972-08-3
D.3.9.3	Other descriptive name	DELTA-9-TETRAHYDROCANNABINOL
D.3.9.4	EV Substance Code	SUB27785
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.7
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CANNABIDIOL
D.3.9.1	CAS number	13956-29-1
D.3.9.3	Other descriptive name	CANNABIDIOL
D.3.9.4	EV Substance Code	SUB26600
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	botanical drug product

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oromucosal spray
D.8.4	Route of administration of the placebo	Oromucosal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Clinically significant agitation in Alzheimer's Diseases

E.1.1.1

Medical condition in easily understood language

Clinically significant agitation in Alzheimer's Diseases

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Behaviours [F01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10001499
E.1.2	Term	Agitation mental
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10001497
E.1.2	Term	Agitation
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Feasibility:
To employ a mixed methods approach to explore the feasibility of a definitive multicentre randomized controlled trial (RCT) within residential nursing home settings of Sativex® for treatment of agitation and aggression in AD. Further, our primary objectives will be;

1. To explore rate of recruitment and retention in the target population, including determining facilitators and barriers.

2. To determine whether the cut-off of ‘clinically significant’ agitation for CMAI or NPI-NH influences rate of recruitment fora future confirmatory trial

3. To investigate the acceptability of an oral mucosal method of administration for this indication in terms of compliance and to care home staff in terms of adherence to the titration schedule.

4. To investigate the acceptability of a cannabinoid-based medicine, and explore impact of societal attitudes and stigma within this patient population as part of the qualitative evaluation.

E.2.2

Secondary objectives of the trial

- To estimate the parameters in a sample size for a later RCT for the treatment effect of Sativex® for agitation and aggression in dementia.
- To explore the overall response rate of Sativex® in the trial population, including other neuropsychiatric symptoms, such as sleep disturbances and changes in appetite, and pain relief.
- Explore Actigraphy data for sleep, physical activity and linked to NPS assessments (exploratory analyses) weeks 2-4

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

Sativex for the treatment of agitation in dementia - a qualitative evaluation
Aims:
1. To investigate the acceptability of a cannabinoid-based medicine, and explore impact of societal attitudes and stigma within this patient population as part of the qualitative evaluation.

2. To investigate the acceptability and feasibility of an oral-mucosal method of administration for this indication in this
population

Synopsis:
This study will include a concurrent Qualitative Evaluation (QE) to evaluate contextual factors that may impact implementation in real-world practice. This will be facilitated via recorded semi-structured interviews with nursing home staff & the participant themselves (when possible). Nursing staff will be given an information sheet and asked to sign a consent form specific to the QE; resident consent for QE will be included in the initial consenting process when entering the study. In collaboration with our qualitative expert collaborator, study researchers will develop an interview topic guide that explores attitudes towards cannabis-based medicines; issues/benefits of administering via an oromucosal method in this population; and factors of regular care home activities/procedures that may facilitate or inhibit effective implementation of Sativex® in practice.

Interviews will be conducted before and after treatment phase with the first 20 recruited participants (approximately balanced 10:10 randomly between active & placebo arm to not risk unblinding of researchers). Interviews will be transcribed and analysed using thematic analysis. Summary results will be included within the main study report, and an in-depth qualitative report will be produced separately.

E.3

Principal inclusion criteria

Age: 55-90.

Probable Alzheimer’s Disease diagnosis according to the criteria of National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDSADRDA).

Clinically significant A/A that requires treatment, defined by CMAI >/= 45 (Cohen-Mansfield et al., 1989) and/or NPI-NH Agitation total score >/= 4 (Livingston et al., 2017).

Residential within a nursing home at recruitment to the study with a history of at least 2 weeks behavioural disturbance.

Written and witnessed informed consent from participant (if deemed having mental capacity), or from personal legal representative (next of kin/power of attorney), or from professional legal representative (non R/F member who can attest to knowing prospective participant for significant period of time).
- Informed consent will be sought in this order from these potential sources.

E.4

Principal exclusion criteria

- Anti-psychotic, anti-epileptic, antidepressant, benzodiazepine, lithium or hypnotic dosage alteration in the 2 weeks prior to the start of the study (and must be expected to maintain dosage throughout study).
- ChEIs (donepezil, rivastigmine or galantamine) and/or memantine, dosage alteration in the 6 weeks prior to the start of the study.
- Currently using cannabis-based medicine(s) (defined as being a UK licensed product prescribed by a doctor)
- Concomitant treatment with strong enzyme inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s Wort) and/or CYP3A4 inhibitors
- Hypersensitivity to Sativex® or any of the excipients in the formulation (ethanol anhydrous, Propylene glycol, peppermint oil).
- Severe cardiovascular disease, recent myocardial infarction (‘recency’ determined by study doctor according to clinical significance), uncompensated congestive heart failure and uncontrolled hypertension.
o QT interval by Fredericia (QTcF) greater than 450 will be excluded if ECG conducted
- Severe, unstable or poorly controlled medical illness.
- Renal Impairment as defined by estimated Glomerular Filtration Rate (eGFR) less than 45ml/min
- Hepatic impairment as defined by Alanine aminotransferase (ALT)/ Aspartate aminotransferase (AST) levels 3 times greater than reference value of laboratory (165 IU/L+ for ALT; 150 IU/L+ for AST)
- Any disability that may interfere with the patient completing the study procedure.
- History or family history of schizophrenia, or other psychotic illness; history of severe personality disorder or other significant psychiatric disorder other than depression associated with their underlying condition.
- Delirium, pain or any medical illness as a clear cause of agitation
- Females of child-bearing potential, defined as ‘having experienced menarche and are not permanently sterilised (e.g. by hysterectomy, bilateral salpingectomy and bilateral oophorectomy) or post-menopausal (defined as at least 1 year since last regular menstrual period)’.
- Evidence of ‘suicidality risk’ determined by >0 on Columbia-Suicide Severity Rating Scale (C-SSRS)
- History/current seizure disorder
- History/current of alcohol or other substance abuse
- History of fall(s) within the last 6 months
7.2.1 COVID-19 specific exclusion criteria
- Positive COVID test result within previous 4 weeks
- Currently experiencing CV19 symptoms (continuous cough, high temperature, loss of taste/smell). NB. can be re-screened after 2 weeks

E.5 End points

E.5.1

Primary end point(s)

Feasibility outcomes:

To consent and randomise 60 participants within a 12-month data collection period (equalling a recruitment rate of 5 participants a month).

To follow up at least 75% of those randomised at 4 weeks.

For a minimum of 80% of participants to demonstrate adherence to the allocation.

To estimate a clinically meaningful effect size of at least 0.3

E.5.1.1

Timepoint(s) of evaluation of this end point

Feasibility endpoints will be evaluated at the end of the trial.

E.5.2

Secondary end point(s)

Safety and tolerability:

Tolerability: Assessed by self- & carer-report of side-effects & medication discontinuation.

Safety parameters: Bloods for Haematology (Full blood count and Haemoglobin) and Biochemistry (Urea & Electrolytes, liver function test, thyroid function test, lipid profile); Vital signs: Heart rate and Blood pressure; Physical examination.

Follow up phone calls for self-reported side effects, including incidence of falls and compliance (week 2 and 6).

Neuropsychiatric Symptoms, cognition, pain, quality of life:

Tertiary Endpoints
- Change in CMAI at 2 & 8 weeks
- Neuropsychiatric Inventory – Nursing Home (NPI-NH) 2, 4 & 8 weeks
- Mini Mental State Examination (MMSE) 4 & 8 weeks
- Functional Assessment Staging of Alzheimer’s Disease (FAST) 4 weeks
- Clinical Frailty Scale (CFS) 4 weeks
- Quality of Life with resident 4 & 8 weeks (QOL-AD care home)
- Quality of Life with proxy informant 4 & 8 weeks (QAULID)
- Change in pain; Abbey Pain Scale (APS) 4 weeks
- Adverse Events (from baseline to 8 weeks)
- Serious Adverse Events (from baseline to 8 weeks)
- Physical activity, sedentary behaviour and sleep disturbances from raw accelerometer data (weeks 2-4)
- Co-prescribed psychotropic medications, (from baseline to 8 weeks)
- Number of recorded incidents of aggression, and number of occasions rescue treatment utilised (from baseline to 8 weeks

E.5.2.1

Timepoint(s) of evaluation of this end point

Safety & tolerability:
- ongoing evaluation throughout trial, and end of trial
Neuropsychiatric Symptoms, cognition, pain, quality of life:
- Change in CMAI at 2 & 8 weeks
- NPI-NH - 2, 4 & 8 weeks
- MMSE - 4 & 8 weeks
- FAST - 4 weeks
- CFS - 4 weeks
- QOL-AD with resident 4 & 8 weeks
- QOLID with proxy informant 4 & 8 weeks
- Change in pain; APS - 4 weeks
- Adverse Events (from baseline to 8 weeks)
- Serious Adverse Events (from baseline to 8 weeks)
- Physical activity, sedentary behaviour and sleep disturbances from raw accelerometer data (weeks 2-4)
- Co-prescribed psychotropic medications, - from baseline to 8 weeks
- Number of recorded incidents of aggression, and number of occasions rescue treatment utilised - from baseline to 8 weeks

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Feasibility

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

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

The end of the trial will be defined as database lock following the last patient visit plus an additional six-week period.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

If a participant is deemed to lack mental capacity, a legal representative will be sought to provide consent.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

As a feasibility trial, we cannot confirm efficacy & further will not be able to confidently recommend continued use of intervention. However, if the results of this study strongly suggest a phase III confirmatory trial is feasible and
promising, we will then seek funding for a larger confirmatory trial. If results continue to support an effective therapeutic impact, we will attempt to make it available for patients across the UK following appropriate regulatory processes.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-08-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-08-14

P. End of Trial
P.	End of Trial Status	GB - no longer in EU/EEA

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