Delta-THC in Behavioral Disturbances in Dementia

• Neuropsychiatric Inventory (NPI) [ Time Frame: At day 10 during treatment blocks ] [ Designated as safety issue: No ]
  Improvement in behavior compared to placebo is measured with the NPI, which is the standard measure of Neuro Psychiatric Symptoms in most clinical trials.
• Neuropsychiatric Inventory (NPI) [ Time Frame: At day 3 during treatment blocks ] [ Designated as safety issue: No ]
  Improvement in behavior compared to placebo is measured with the NPI, which is the standard measure of Neuro Psychiatric Symptoms in most clinical trials.
• Neuropsychiatric Inventory (NPI) [ Time Frame: At month 1 during extension phase ] [ Designated as safety issue: No ]
  Improvement in behavior during long term treatment is measured with the NPI, which is the standard measure of Neuro Psychiatric Symptoms in most clinical trials.
• Neuropsychiatric Inventory (NPI) [ Time Frame: At month 3 during extension phase ] [ Designated as safety issue: No ]
  Improvement in behavior during long term treatment is measured with the NPI, which is the standard measure of Neuro Psychiatric Symptoms in most clinical trials.
• Neuropsychiatric Inventory (NPI) [ Time Frame: At month 6 during extension phase ] [ Designated as safety issue: No ]
  Improvement in behavior during long term treatment is measured with the NPI, which is the standard measure of Neuro Psychiatric Symptoms in most clinical trials.

• Cohen-Mansfield Agitation Inventory (CMAI) [ Time Frame: At days 1, 3, 8, and 10 during treatment blocks 1 and 4 and weekly during treatment blocks 2, 3, 5 and 6 and months 1, 3, 6 and 6 during extension phase ] [ Designated as safety issue: No ]
  Improvement in agitation compared to placebo and during long term treatment is measured with CMAI. It is useful in determining fluctuations in behaviors and emotional states in Alzheimer's Disease
• Zarit Burden Scale (ZBS) [ Time Frame: At days 3 and 10 during treatment blocks and months 1, 3 and 6 during extension phase ] [ Designated as safety issue: No ]
  Reducing caregiver stress compared to placebo and during long term treatment by focusing on the patients' behavior compared to Zarit burden interviews with the caregiver.
• Visual Analogue Scale (VAS) Bowdle for feeling high [ Time Frame: At days 1, 3, 8, and 10 during treatment blocks 1 and 4 and weekly during treatment blocks 2, 3, 5 and 6 and months 1, 3, 6 and 6 during extension phase ] [ Designated as safety issue: Yes ]
  severity and duration of feeling high episodes
• Gait rite® [ Time Frame: At days 1 and 8 during blocks 1 and 4 and at 1, 3 and 6 months during extension phase ] [ Designated as safety issue: Yes ]
  Improvement and/or safety compared to placebo and during long term treatment on balance and mobility. It is a non invasive and highly feasible mobility assessment.
• Sway Star® [ Time Frame: At days 1 and 8 during blocks 1 and 4 and at 1, 3 and 6 months during extension phase ] [ Designated as safety issue: Yes ]
  Improvement and/or safety compared to placebo and during long term treatment on balance and mobility. It is a non invasive and highly feasible mobility assessments.
• Time up and go [ Time Frame: At days 1, 3, 8, and 10 during treatment blocks 1 and 4 and weekly during treatment blocks 2, 3, 5 and 6 and months 1, 3, 6 and 6 during extension phase ] [ Designated as safety issue: Yes ]
  Improvement and/or safety compared to placebo and during long term treatment on balance and mobility in elderly patients.
• Tinetti [ Time Frame: At days 1, 3, 8, and 10 during treatment blocks 1 and 4 and weekly during treatment blocks 2, 3, 5 and 6 and months 1, 3, 6 and 6 during extension phase ] [ Designated as safety issue: Yes ]
  Improvement and/or safety compared to placebo and during long term treatment on balance and mobility in elderly patients. It is a performance-oriented assessment of mobility problems in elderly patients.
• pharmacogenetics [ Time Frame: day 1 ] [ Designated as safety issue: No ]

  The following polymorphisms will be genotyped:

  • CYP2C9*2
  • CYP2C9*3
  • CYP2C19*2
  • CYP2C19*3
  • CYP2C19*17

  To investigate the role of CYP2C9 and CYP2C19 genetic polymorphisms in the interindividual variation in pharmacokinetics, efficacy and adverse events of THC.

• Cohen-Mansfield Agitation Inventory (CMAI) [ Time Frame: At days 1, 2, 3, 8, 9 and 10 during treatment blocks and months 1, 3 and 6 during extension phase ] [ Designated as safety issue: No ]
  Improvement in agitation compared to placebo and during long term treatment is measured with CMAI. It is useful in determining fluctuations in behaviors and emotional states in Alzheimer's Disease
• Zarit Burden Scale (ZBS) [ Time Frame: At days 3 and 10 during treatment blocks and months 1, 3 and 6 during extension phase ] [ Designated as safety issue: No ]
  Reducing caregiver stress compared to placebo and during long term treatment by focusing on the patients' behavior compared to Zarit burden interviews with the caregiver.
• Delirium Observation Screening Scale (DOS) [ Time Frame: At days 1, 2, 3, 8, 9 and 10 during treatment blocks ] [ Designated as safety issue: Yes ]
  severity and duration of delirium
• Visual Analogue Scale (VAS) Bowdle for feeling high [ Time Frame: At days 1, 2, 3, 8, 9 and 10 during treatment blocks and months 1, 3, 6 and 6.5 during extension phase ] [ Designated as safety issue: Yes ]
  severity and duration of feeling high episodes
• Gait rite® [ Time Frame: At days 2 and 9 during hospital admission and at months 1, 3 and 6 during extension phase ] [ Designated as safety issue: Yes ]
  Improvement and/or safety compared to placebo and during long term treatment on balance and mobility. It is a non invasive and highly feasible mobility assessments.
• Sway Star® [ Time Frame: At days 2 and 9 during hospital admission and at months 1, 3 and 6 during extension phase ] [ Designated as safety issue: Yes ]
  Improvement and/or safety compared to placebo and during long term treatment on balance and mobility. It is a non invasive and highly feasible mobility assessments.
• Time up and go [ Time Frame: At days 1, 2, 3, 8, 9 and 10 during treatment blocks and months 1, 3 and 6 during extension phase ] [ Designated as safety issue: Yes ]
  Improvement and/or safety compared to placebo and during long term treatment on balance and mobility in elderly patients.
• Tinetti [ Time Frame: At days 1, 2, 3, 8, 9 and 10 during treatment blocks and months 1, 3 and 6 during extension phase ] [ Designated as safety issue: Yes ]
  Improvement and/or safety compared to placebo and during long term treatment on balance and mobility in elderly patients. It is a performance-oriented assessment of mobility problems in elderly patients.

Dementia is a common chronic condition, with predicted increasing prevalence. Nearly all patients with dementia will experience neuropsychiatric symptoms (NPS). This causes significant burden for the individual patients and their caregivers. Current treatment has only modest efficacy and important side-effects. Formulations with Δ9-tetrahydrocannabinol (THC), the psycho-active compound of cannabis, are currently being registered for spasms in multiple sclerosis and other diseases, and may have beneficial effects on NPS.

Design Phase II pilot study, multi-center, repeated cross-over, double blinded randomized trial. Consisting out of 6 blocks of 2 weeks, after 3 blocks (period A) the dose will increase after safety evaluation by the physician responsible for the patient. Each block consists out of active treatment and placebo, within between a wash-out period. After the two treatment periods, subjects will proceed to the extension phase if applicable.

Study centers The department of Geriatrics from Radboud University Nijmegen Medical Centre and the department of Elderly from Vincent van Gogh voor Geestelijke Gezondheidszorg Venray (VVG) will participate in this multi center study.

Participants 20 subjects with dementia and NPS. Intervention Namisol® in doses of twice daily 0,75 mg tablet (period A) and twice daily 1.5 mg (period B) THC oral tablets. Placebo of twice daily 0,75 mg and twice daily 1.5 mg oral tablets Outcome measures Primary outcome is NPI score, secondary CMAI, Zarit Burden scale. Other outcomes include vital signs, side-effects, physical exam, mobility and pharmacogenetics.

Visits This study will be assessed fully ambulatory, starting with a 5 hour clinical visit on day 1 and 8 of block 1 and a phone call on day 2 and 9 for assessment of Adverse Events. Furthermore, the research physician will conduct a weekly home visit weekly during the crossover phase for assessment of , among others, the primary outcome measure. These visits will all be repeated in period B of the crossover phase.

During the 6 month open label extension phase, subjects will visit the clinic three times.

• Drug: Delta-THC
  First treatment period: During 3 days of hospital admission, 2 times daily 1 tablet of 0.75 mg delta-THC will be administered after which a 4 day washout period applies. Thereafter the cross over starts. This will be repeated two times but then without hospital admission.
  Other Names:

  • Namisol
  • Cannabis
  • ECP002A
• Drug: Delta-THC
  If first treatment period is safe, the second treatment period starts: during 3 days of hospital admission, 2 times daily 1 tablet of 1.5 mg delta-THC will be administered after which a 4 day washout period applies. Thereafter the cross over starts. This will be repeated two times but then without hospital admission.
  Other Names:

  • Namisol
  • Cannabis
  • ECP002A
• Drug: placebo
  During 3 days of hospital admission, 2 times daily 1 tablet of placebo will be administered after which a 4 day washout period applies. Thereafter the cross over starts. This will be repeated two times but then without hospital admission during the first treatment period. If the first period appeared to be safe, this same intervention will be repeated during the second treatment period.
  Other Name: Placebo Namisol
• Drug: Delta-THC
  In case either 2 times daily 1 tablet 0,75mg or 2 times daily 1 tablet 1.5mg Delta-THC appeared to be efficacious for a particular patient, this patient can continue the effective dose of delta-THC in an open label extension phase during 6 months.
  Other Names:

  • Namisol
  • Cannabis
  • ECP002A

• Active Comparator: Delta-THC
  At hospital admission Delta-THC will be administered during three days.
  Interventions:

  • Drug: Delta-THC
  • Drug: Delta-THC
  • Drug: Delta-THC
• Placebo Comparator: placebo
  At hospital admission placebo will be administered during three days.
  Intervention: Drug: placebo

Inclusion Criteria:

• Diagnosis of Alzheimer's Disease (AD), Vascular Dementia (VD) or mixed, according to the criteria of NINCDS-ADRDA or NINCDS-AIREN
• Clinical Dementia Rating score between 0.5 and 3
• NPS symptoms, with at least agitation or aggression

Exclusion Criteria:

• Diagnosis of Lewy Body Dementia (LBD) or Fronto-Temporal Dementia (FTD)
• Major psychiatric disorder
• Severe concomitant illness, seizure, arrhythmias (except sinus arrhythmia and atrial fibrillation), heart failure New York Heart Association (NYHA) class III or IV
• Tri Cyclic Antidepressives (TCA) or opioids used within 30 days before randomization till the end of the study
• Changes in dosage of antidepressives within 6 weeks before randomization and during study, and changes in dosage antipsychotics or benzodiazepines within 2 weeks prior to randomization and during study