Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment.

BACKGROUND: Niemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptosomes, suggesting it plays a role in lysosomal degradation pathway and in synaptic transmission. Neuronal function is especially vulnerable to NPC1 deficiency and synaptic changes seem a key element in disease development. Currently, Miglustat (Zavesca®) is the only approved treatment for NPC. However, preclinical evidence showed that low-dose Efavirenz reverted synaptic defects through pharmacological activation of the enzyme CYP46. METHODS: This is a single-center, phase II clinical trial to evaluate the efficacy and safety of Efavirenz in addition to standard of care in patients diagnosed with adult or late juvenile-onset NPC with cognitive impairment. All enrolled patients will be treated orally with 25 mg/d of Efavirenz for 52 weeks (1 year). Secondary objectives include evaluating clinical (neurological and neuropsychological questionnaires) and biological (imaging and biochemical biomarkers) parameters. DISCUSSION: NPC is still an unmet medical need. Although different therapeutic approaches are under study, this is the first clinical trial (to the best of our knowledge) studying the effects of Efavirenz in adult- and late-juvenile-onset NPC. Despite the small sample size and the single-arm design, we expect the results to show Efavirenz's capacity of activating the CYP46 enzyme to compensate for NPC1 deficiency and correct synaptic changes, therefore compensating cognitive and psychiatric changes in these patients. This study may provide direct benefit to enrolled patients in terms of slowing down the disease progression.

Severity of dementia, anosognosia, and depression in relation to the quality of life of patients with Alzheimer disease: discrepancies between patients and caregivers.

OBJECTIVE: To investigate the factors associated with discrepancies between patient and caregiver reports of the quality of life of patients (QoLp) with Alzheimer disease. METHODS: Cross-sectional analytic study of 141 patients and their caregivers. The instruments used were the Quality of Life in AD, the Global Deterioration Scale (GDS), the Geriatric Depression Scale, and the Anosognosia Questionnaire-Dementia. Differences were analyzed according to GDS stage. A linear regression analysis was conducted using the difference between the absolute QoLp scores of patients and caregivers. A cluster analysis involving patient variables was then performed. RESULTS: The discrepancy between patient and caregiver QoLp ratings increased in line with GDS stages (χ(2) (2) = 8.7, p = 0.013). In the regression model (F [7,133] = 16.6, p <0.001; R(2) = 0.477), discrepancies in QoLp reports were associated with greater anosognosia, less depression, and a better cognitive status in patients and with female gender among caregivers. The cluster analysis showed that patients with the lowest ratings of QoLp had a better cognitive status, more depression, and less anosognosia. Conversely, the highest ratings were given by patients with a poorer cognitive status, less depression, and greater anosognosia. CONCLUSIONS: The factors associated with greater discrepancies between patient and caregiver ratings of QoLp were severity of dementia, anosognosia, depression, and cognitive status in patients and female gender in caregivers. In patients with advanced dementia, greater anosognosia leads to more positive ratings in QoLp and complementary observations are required.