Delta-THC in Behavioral Disturbances in Dementia

Study Overview
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Brief Summary
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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.

Detailed Description
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Design Phase II pilot study, multi-center, repeated cross-over, double blinded randomized trial. The study consists of two weeks baseline measurements to assure that the neuropsychiatric symptoms are stable and six successive treatment blocks of 2 weeks. Each treatment block lasts for two weeks and contains two double-blinded drug periods, each lasting three days of oral THC or placebo, separated by four day washout periods. After three treatment blocks (period A), the dosage of active treatment was increased for the latter three treatment blocks (period B). 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.

Official Title
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Two Phase, Repeated Crossover Study With Dose Escalation on Delta(9)-Tetrahydrocannabinol (Delta-THC) in Behavioral Disturbances in Dementia

Conditions
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Dementia

Intervention / Treatment
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* Drug: Delta-THC
* Drug: placebo
* Drug: Delta-THC


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Delta-THC<br>THC will be administered twice daily during three consecutive days per treatment block(0.75 or 1.5 mg twice daily) | Drug: Delta-THC<br>* Active treatment consists of THC in tablet form. Patients receive 0.75 mg THC twice daily during the first three treatment blocks (period A) and 1.5 mg THC twice daily during the latter three treatment blocks (period B). Placebo treatment consists of two tablets daily and is matched to the active treatment for taste, color and size. Study medication will be administered at 10 a.m. and 4 p.m., by the primary caregiver. These time points are chosen because NPS often occur later on the day, when fatigue and external signals build up to the stress and result in NPS. The order of administration of THC and placebo (1:1) will be determined by randomization per block: THC followed by placebo or placebo followed by THC.<br>* Other names: ECP002A;Drug: Delta-THC<br>* 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.<br>* Other names: ECP002A;|
| Placebo Comparator: placebo<br>Placebo will be administered twice daily during three consecutive days per treatment block. | Drug: placebo<br>* Active treatment consists of THC in tablet form. Patients receive 0.75 mg THC twice daily during the first three treatment blocks (period A) and 1.5 mg THC twice daily during the latter three treatment blocks (period B). Placebo treatment consists of two tablets daily and is matched to the active treatment for taste, color and size. Study medication will be administered at 10 a.m. and 4 p.m., by the primary caregiver. These time points are chosen because NPS often occur later on the day, when fatigue and external signals build up to the stress and result in NPS. The order of administration of THC and placebo (1:1) will be determined by randomization per block: THC followed by placebo or placebo followed by THC.<br>* Other names: Placebo Namisol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuropsychiatric Inventory (NPI) | Improvement in behavior compared to placebo is measured with the NPI, which is the standard measure of Neuro Psychiatric Symptoms in most clinical trials. | At day 3 and 10 during treatment blocks and after 1 month, 3 months and 6 months in the open label extension phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohen-Mansfield Agitation Inventory (CMAI) | 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 | 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 | 
| Zarit Burden Scale (ZBS) | 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. | At days 3 and 10 during treatment blocks and months 1, 3 and 6 during extension phase | 
| Visual Analogue Scale (VAS) Bowdle for feeling high | severity and duration of feeling high episodes | 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 | 
| Gait rite® | 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. | At days 1 and 8 during blocks 1 and 4 and at 1, 3 and 6 months during extension phase | 
| Sway Star® | 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. | At days 1 and 8 during blocks 1 and 4 and at 1, 3 and 6 months during extension phase | 
| Time up and go | Improvement and/or safety compared to placebo and during long term treatment on balance and mobility in elderly patients. | 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 | 
| Tinetti Balance Assessment Tool | 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. | 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 | 
| pharmacogenetics | 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. | day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dementia, Alzheimer, Cannabis, THC, Behavioral Disturbances, Neuropsychiatric Inventory