Efficacy and safety of delta-9-tetrahydrocannabinol (delta-THC) in behavioural disturbances in dementia

The prevalence of Alzheimer*s disease (AD) is estimated to exceed 35 million
worldwide and this will increase to 42 million by 2020. With this increasing
prevalence, there will also be a substantial increase in patients with dementia
who suffer from behavioural disturbances, such as agitation, aggression or
aberrant motor behaviour. These symptoms are summerized as neuropsychiatric
symptoms (NPS). NPS reduce patient's cognitive functioning and quality of life
and increase caregiver's burden. NPS are often treated with antipsychotic drugs
(APs). APs have only a modest efficacy and important side-effects, which result
in extrapiramidal symptoms and increased risk of morbidity and mortality.
Persistent pain can cause NPS. Due to a decreased cognitive and communicative
ability, pain is often expressed in behavioural changes, such as repetitive
movements, vocalizations and wandering. Alterations in pharmacokinetics, pain
perception, communication and concurrent medication asks for an adequate and
safe drug treatment in these older and frail patients.

There is evidence that THC has a positive effect on NPS. Unfortunately, there
are only few trials studying the efficacy of THC in dementie patients. The
cannabinoid agonist dronabinol (containing THC) was first found to improve
agitation and appetite in dementia. Furthermore, several clinical studies show
that cannabinoids are effective in treatment of neuropathic pain and spasticity
in patients with Multiple Sclerosis (MS). Unfortunately, to our knowledge, no
previous studies have been conducted to assess the efficacy of cannabinoids on
pain in dementia patients.

The high prevalence of behavioural disturbances in persons with dementia, a
clear interaction with persistent pain, the lack of appropriate drugs for
treating this problem and the positive suggestions from preliminary clinical
studies with THC directly fuel the study presented here. This will be a phase
II study in which the efficacy and safety of Namisol® (a tablet with THC)
behavioural disturbances in dementia patients will be evaluated. Secondarily,
we will evaluate the effiacy on persistent pain in a subgroup of particpants.

The primary objective is to evaluate the efficacy of Namisol® in the management
of behavioural disturbances in patients with dementia.

Secondary objectives are:
- To evaluate the efficacy of Namisol® on secondary outcome measures, such as
quality of life and functioning.
- To evaluate safety of Namisol® in this subject group, as assessed with
physical examination and adverse event monitoring.
- For the subgroup of subjects suffering from pain: to evaluate the efficacy of
Namisol® pain intensity.

It is hypothesized that Namisol® will lead to more reduction in NPS than
placebo, as assessed with the neuropsychiatric inventory (NPI), especially on
the domains agitation/aggression and motor disturbance. We expect this to be
primarily due to psychoactive effects of Namisol® and secondary to a reduction
in pain sensation. It is expected that behavioural disturbances will lead to
better functioning in daily living and quality of life.

This is a randomized placebo-controlled double-blind parallel-group multicentre
study

Subjects who appear to fulfill the eligibility criteria are informed about the
study. After signing informed consent, a screening visit will take place.
Subjects who are eligible for participation enter a wash-out period, for
discontinuation of their own analgesic medication (only if applicable).
Acetaminophen (PCT) 1000 mg three times daily will be started in this wash-out
period, independent of the occurrence of pain complaints. Subjects will be
randomly allocated to receive one of the two interventions (Namisol® 1.5 mg and
PCT 1000 mg three times daily, or placebo and PCT 1000 mg three times daily)
for a double-blind intervention period of three weeks. After two weeks
treatment (day 14) the NPI and CCGIC will be assessed by telephone interview
with the caregiver. Subjects and their caregivers visit the site twice (at
baseline (day 0) and after three weeks treatment (day 21)) for assessments of
the outcome parameters. For the purpose of compliance and safety, there will
also be three phone calls, performed by the researcher during the intervention
period. After completion of this intervention period subject*s own analgesic
treatment will be restarted (if applicable). A follow up phone call will follow
two weeks after last study medication intake for assessment of adverse events
and pain complaints.

Intervention phase:
first study arm: delta-9-THC (Namisol®) 1.5 mg three times daily +
acetaminophen 1000 mg three times daily for a period of three weeks
second study arm: placebo (tablet) three times daily + acetaminophen 1000 mg
three times daily for a period of three weeks

THC is already widely used, among other indications as a registered analgetica
in MS patients. THC is also used as study drug in dementia patients, which has
resulted in a therapeutic effect in this patient group. Due to the current
extensive knowledge of THC, it can be stated that the drug related risks are
limited. Moreover, the current study will use significantly lower dosages of
THC compared to the conducted studies.
Possible side effects (as described in the Investigator Brochure) are:
- dizziness
- somnolence
- tachycardia
- euforia
- changes in blood pressure (not specified)
It should be noted that older people are likely more sensitive to the
psychoactive effects and effects on blood pressure.

Subjects and caregiver's burden mainly consists of several visits to the
outpatient clinic. During this visit, mainly questionnaires will be conducted.
During treatment at home, the subject will be asked to report their medication
intake, side effects and pain intensity daily. The caregiver will be asked to
assist the subject. The burden is believed to be proportional in relation to
the considered problem for which this trial is instituted.
The burden of behavioural problems in dementia can be very large, for both
patient and caregiver. This leads to a high disease related distress.