Table 3.
Summary of completed clinical trials evaluating drug candidates in psychosis, aggression, and agitation associated with dementia and Alzheimer’s disease (AD)
| Drug/indication | Trial identifier | Study design | Results | |||
|---|---|---|---|---|---|---|
| Participants | Dosing paradigm | Study design | Primary outcome measure | |||
| Pimavanserin/psychosis in AD | NCT02035553 [57] | 181 patients with AD | 34 mg/day for 12 weeks | Phase II, single-center, double-blind, placebo-controlled | Change from baseline to week 6 in the NPI-NH psychosis score | Statistically superior effect of pimavanserin compared with placebo at the primary endpoint (week 6), with an acceptable tolerability profile and no negative effect on cognition (week 12) [58] |
| Pimavanserin/agitation and aggression in AD | NCT03118947 [56] | 79 patients with AD | 20 mg/day or 34 mg/day for 52 weeks | Phase II, open-label, single-group | TEAEs, safety and tolerability of pimavanserin after 52 weeks of treatment | Results not available yet |
| Eltoprazine/aggression in AD | H.134.5012 [52] GDCT0252614a | 29 patients with SDAT or mixed SDAT/multi-infarct dementia | 5–10 mg/day for 4 weeks | Phase II, multi-center, double-blind, randomized, placebo-controlled | Social Dysfunction and Aggression Scale and the Staff Observation Scale after 4 weeks | Significant improvement of aggressive behavior within the eltoprazine-treated group compared with the placebo group [52] |
| Citalopram/agitation in AD | NCT00898807 [191] | 186 patients with AD | 10–30 mg/day for > 3 weeks (based on response and tolerability) | Phase III, randomized, multi-center, placebo-controlled, double-blind | Evaluated by NBRS-A and mADCS-CGIC at week 9 | Clinically meaningful reduction in the AD-associated agitation compared with placebo. [103] Cognitive and cardiac adverse effects associated with citalopram treatment |
| Escitalopram/psychotic symptoms and agitation in AD | NCT 01119638 [109] | 40 patients with AD | Escitalopram/risperidone 5–10 mg/day and 0.5–1.0 mg/day for 6 weeks | Phase IV, randomized, double-blind, single-center, pilot | Change in the total score on NPI (week 6) | Escitalopram and risperidone were equally effective in reducing psychotic symptoms and agitation [110] |
| Mirtazapine/agitation in AD | Pilot study [176] | 16 patients with AD | 15–30 mg/day for 12 weeks | Open-label, prospective | Changes in behavior were assessed using CMAI-SF (2, 8, and 12 weeks) | Significant reduction in CMAI-SF and CGI-S between pre- and post-treatment with mirtazapine [176]. No significant side effect and cognitive deterioration |
| Prazosin/agitation and aggression in AD | Pilot study [151] | 22 patients with AD | Mean dose: 5.7 mg/day for 8 weeks | Double-blind, placebo-controlled, randomized | Improvement on BPRS and NPI at weeks 1, 2, 4, 6, and 8 | Significant improvements in the NPI and BPRS within the prazosin-treated group compared with the placebo group [151] |
| Brexpiprazole/agitation in AD | NCT01862640 [192] | 433 patients with AD | 1 and 2 mg/day for 12 weeks | Phase III, randomized, double-blind, placebo-controlled, multi-center | Change in the CMAI total score (baseline to week 12). The secondary outcome is the change in the CGI-S score | The improvements in the primary endpoint of CMAI for brexpiprazole 2 mg were statistically better than placebo and appeared more robust than the improvements on the key secondary endpoint of CGI-S [114] |
| Brexpiprazole/agitation in AD | NCT01922258 [193] | 270 patients with AD | A flexible dose range: 0.5 mg/day, 1 mg/day, or 2 mg/day for 12 weeks | Phase III, randomized, double-blind, placebo-controlled, multi-center | Change in the CMAI total score (baseline to week 12). The secondary outcome is the change in the CGI-S score | The improvements in the primary endpoint of CMAI appeared less robust than the improvements on the key secondary endpoint of CGI-S [114] |
| Lumateperone/agitation in AD | NCT02817906 [119] | 177 patients with AD | 9 mg/day for 4 weeks | Phase III, randomized, double-blind, placebo-controlled, multi-center | CMAI-C (week 4) | Terminated (pre-specified interim analysis indicated futility) [119] |
| THC/dementia-related neuropsychiatric symptoms (agitation, aggression, or aberrant motor behavior) | NCT01608217 [194] | 50 patients diagnosed with AD, vascular dementia, or mixed dementia | 4.5 mg/day for 3 weeks | Phase II, randomized, double-blind, placebo-controlled study, multi-center | NPI assessed at baseline and after 14 and 21 days | No significant difference in reduction from baseline between THC and placebo [163] |
| THC/dementia-related neuropsychiatric symptoms with at least agitation or aggression | NCT01302340 [195] | 22 patients with AD, vascular dementia, or mixed dementia |
Period A: 1.5 mg/day for 6 weeks Period B: 3 mg/dayb for 6 weeks |
Phase II, repeated crossover, randomized, double-blind, placebo-controlled, multi-center | Change in NPI score (at day 3 and 10 during treatment blocks and after 1 month) |
No benefit of THC treatment (0.75 mg and 1.5 mg twice daily) on neuropsychiatric symptoms in dementia [164] |
| Dronabiol/dementia-related behavioral disturbances (aggression, agitation) | Retrospective study | 40 patients with dementia | 7.03 mg daily for 16 days | Retrospective | PAS (at day 7) | Total PAS score decreased significantly during dronabinol treatment [165] |
| Dronabiol/night-time agitation in dementia | Open-label pilot study | 6 patients diagnosed with late-stage dementia (5 with AD, 1 with vascular dementia) | 2.5 mg daily for 2 weeks | Open-label pilot | NPI, Actiwatch (at day 5) | Dronabinol led to a reduction in nocturnal motor activity [167] |
| Nabilone/agitation in AD | NCT02351882 [59] | 39 patients with AD | 1–2 mg for 14 weeksc | Phase II/III, pilot, randomized, double-blind, crossover | Change in agitation; CMAI (after 14 weeks) |
Significant reduction in agitation over 6 weeks in the nabilone group. [60, 61] Sedation occurred during treatment with nabilone |
| AVP-923 (dextromethorphan/quinidine)/agitation in AD | NCT01584440 [196] | 220 patients with AD | Dextromethorphan/quinidine at doses of 20 mg/10 mg once daily to 30 mg/10 mg twice daily for 10 weeks | Phase II randomized, multi-center, double-blind, placebo-controlled | Change from baseline in NPI Agitation/Aggression domain score (10 weeks) | Significant improvement on NPI, Agitation/Aggression score compared with placebo [128] |
BPRS Brief Psychiatric Rating Scale, CGI-S Clinical Global Impression-Severity of Illness, CMAI Cohen-Mansfield Agitation Inventory, CMAI-C Cohen-Mansfield Agitation Inventory-Community, CMAI-SF Cohen-Mansfield Agitation Inventory-Short Form, mADCS-CGIC modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change, NBRS-A Neurobehavioral Rating Scale Agitation subscale, NPI Neuropsychiatric Inventory, NPI-NH Neuropsychiatric Inventory Nursing Home Version scale, PAS Pittsburgh Agitation Scale, SDAT senile dementia of Alzheimer’s type, TEAEs treatment-emergent adverse events, THC Δ-9-tetrahydrocannabinol
aGDCT trial identifier provided by GlobalData
bPeriod A (6 weeks): 0.75 mg of THC twice daily for 3 successive days, separated by a 4-day washout. Period B: 1.5 mg of THC twice daily for 3 successive days, separated by a 4-day washout period
c14-week, randomized, double-blind, crossover trial compared nabilone to placebo (6 weeks each) with a 1-week washout between phases