Clinical trials in dementia with propentofylline. A 12-month, randomized, placebo-controlled trial of propentofylline (HWA 285) in patients with dementia according to DSM III-R. The European Propentofylline Study Group. Clinical trials of propentofylline in vascular dementia. European/Canadian Propentofylline Study Group. Propentofylline treatment for Alzheimer disease and vascular dementia: an economic evaluation based on functional abilities. Propentofylline improves regional cerebral glucose metabolism and neuropsychologic performance in vascular dementia. Propentofylline enhances cerebral metabolic response to auditory memory stimulation in Alzheimer's disease. Propentofylline in adult-onset cognitive disorders: double-blind, placebo-controlled, clinical, psychometric and brain mapping studies. Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe.
The mode of action of propentofylline (a xanthine derivative) suggested that it would have beneficial effects in patients with Alzheimer's disease or vascular dementia. In four double-blind, placebo-controlled, randomized studies, 901 patients with mild to moderate Alzheimer's disease and 359 patients with mild to moderate vascular dementia were treated for up to 12 months (daily dose of propentofylline: 3 x 300 mg taken 1 hr before food). Patients were assessed at regular intervals for efficacy and safety of the drug. Efficacy variables covered cognitive and global functions as well as activities of daily living. Propentofylline showed statistically significant, clinically relevant improvements over placebo in efficacy assessments, both in patients with Alzheimer's disease and in patients with vascular dementia. The drug was also well tolerated. It had no significant effects on laboratory findings and the adverse events that were considered to be related to the study medication were mostly minor, transient, and affected the digestive and nervous systems. Alzheimer's disease (AD) and vascular dementia (VaD) share several features such as overactivation of microglial cells, damage induced by free radicals, glutamate and calcium overload. Propentofylline (HWA 285) has shown beneficial effects on all of these common elements, thus favouring its use in both subtypes of dementia. In a multinational, randomized, 12-month, double-blind, parallel-group study 260 out-patients with mild to moderate AD or VaD received 300 mg propentofylline (n = 129) or placebo (n = 131) three times daily 1 h before meals. The efficacy was tested at four independent rater levels (physician, psychologist, relative and patient) with assessments covering three major domains of dementia (global function, cognitive function and activities of daily living). After 12 months, the total patient population showed statistically significant treatment differences in favour of propentofylline for the global measures of dementia (Gottfries-Bråne-Steen scale, GBS, p = 0.001; Clinical Global Impressions, CGI, item I: p = 0.004, item II: p = 0.072) as well as for the cognitive measures (Syndrome Short Test, SKT, p = 0.002) and Mini-Mental State Examination (p = 0.001). The activities of daily living also showed a significant treatment difference in favour of propentofylline (p = 0.002). No significant treatment differences were found for rating scales performed by the patients. At month 12, VaD patients showed treatment differences in favour of propentofylline for the GBS total score (p = 0.006), CGI item I (p = 0.004), GGI item II (p = 0.044) and SKT (p = 0.028). Treatment differences for AD patients were all in favour of propentofylline and reached statistical significance for the SKT (p = 0.018). Propentofylline showed a good safety profile with respect to adverse events, vital signs, ECG and laboratory changes. The neuroprotective glial cell modulator propentofylline has been used in clinical trials involving more than 800 patients with vascular dementia (VaD). These data derive from two sources: a pooled group of VaD patients from four early phase III European trials, and a multinational European/Canadian phase III study (MN 305) that features a combined randomized withdrawal/delayed onset of progression design to evaluate the effect of propentofylline on disease progression. In the pooled studies, DSM-III-R criteria, Hachinski Ischemia Scores, computed tomography (CT), and magnetic resonance imaging (MRI) were used to select subjects with mild-to-moderate disease; in MN 305, National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria and neurologic examinations (including CT and MRI scans) were used to select patients with possible or probable VaD. The use of a central rater to assess cerebrovascular disease in neuroradiologic examinations for study MN 305 was considered to be a key feature for reducing the heterogeneity of the VaD patient population. In addition, the inclusion of patients with possible VaD in this trial greatly increased the number of eligible patients; subgroup analyses revealed no substantial differences between patients with probable versus possible VaD, justifying their inclusion in the study. VaD patients exhibited a more pronounced placebo response in global assessments compared with the Alzheimer disease population in a parallel study. In addition, they experienced less deterioration over time with respect to cognitive and global assessments. Beneficial effects of propentofylline were consistently demonstrated in the domains of cognitive and global function for both VaD populations; however, no treatment benefits could be demonstrated for activities of daily living, possibly due to factors relating to the study population/design, the lack of a validated test instrument for such patients, the caregiver-related phenomenon of "tutoring," or the nature of the disease itself. A Canadian economic evaluation of propentofylline (a therapy shown to be effective for patients with mild to moderate Alzheimer disease and/or vascular dementia) versus standard care was conducted. Patients were categorized by functional abilities according to the Alberta Resident Classification System by translating measures that were originally captured through the Gottfries-Bråne-Steen scale. The Alberta Resident Classification System was then linked to a community dataset of home care costs for a population with dementia. Cost and cost-effectiveness analyses were performed from the perspective of the Ministry of Health, the caregiver, and society using an intent-to-treat analysis for propentofylline versus placebo. Results, limited to the 48-week clinical trial duration, indicated that propentofylline improved health outcomes of persons with dementia as statistically significant treatment effects were found. However, although an incremental cost for the propentofylline intervention was incurred from the Ministry of Health perspective, home care and, to a larger extent, caregiver costs were reduced. Savings in these areas may have partially offset annual treatment medication costs because a non-statistically significant cost difference was observed from a societal perspective. In a double-blind, placebo-controlled trial in thirty patients with mild to moderate vascular dementia (VD) according to DSM-III-R criteria, the effects of the adenosine uptake blocker propentofylline (HWA 285) on regional cerebral glucose metabolism (rCMRGl) was studied using positron emission tomography of 2-[18F]fluoro-2-deoxy-D-glucose (FDG). 25 subjects completed the 3-months study. Propentofylline significantly improved relative rCMRGl in the motor cortex, while relative rCMRGl in the placebo treated group worsened significantly. Neuropsychologically, visual information processing was improved in the propentofylline group and we observed a trend towards a slowing of the progression of cognitive deterioration in patients with VD. The results of the longitudinal analysis showed further that neuropsychological and metabolic changes are closely related. These findings justify a large-scale clinical trial to prove therapeutic efficacy. To evaluate efficacy, safety, metabolic and clinical effects of propentofylline in Alzheimer's disease (AD), a prospective, randomized, double-blind, placebo-controlled trial was performed in 30 patients with mild to moderate AD who underwent pretreatment and posttreatment 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography under resting conditions and during stimulation with an auditory memory paradigm. Twenty-eight subjects completed the 3-month study. The drug was well tolerated. In the active treatment group, a significant increase of cerebral metabolic response to the memory task was observed (multiple measurement ANOVA P = 0.02). The placebo group showed a significantly decline in the MMSE score (P = 0.02) while there was no change in the treatment group. This suggests a protective role for propentofylline in slowing the progression of AD. In a double-blind, placebo-controlled parallel group trial, the therapeutic efficacy and central effects of propentofylline (HWA 285) - a xanthine derivative with neuroprotective, metabolic, hemorheologic and antithrombotic action - were studied in 190 elderly outpatients with mild to moderate chronic cognitive disturbances (mild dementia, DSM-III-R). They received after a 2-week run-in period (placebo) for 12 weeks either 3 x 300 mg propentofylline or 3 x 1 tablet placebo (given at least 1 h before meals). The verum group (n = 96, age 68 +/- 9) was comparable to the placebo group (n = 94, age 69 +/- 8) in regard to age, height, smoking, consumption of stimulating alcoholic drinks, family and living status. Clinical evaluation by the Gottfries-Brane-Steen (GBS) scale demonstrated a significant superiority of propentofylline over placebo in the total score and the four GBS factors (motor, intellectual, emotional functions and other symptoms) as well as in the clinical global impression and Mini-Mental State. Psychometric measures showed slight and significant improvement in both groups but no intergroup differences. EEG brain mapping was carried out before and after 12 weeks' treatment in the Viennese subsample involving 24 propentofylline and 24 placebo patients. Propentofylline-treated patients exhibited, as compared with placebo-treated ones, a trend towards augmentation of total power, furthermore an increase in relative delta and beta and a decrease in alpha power, an acceleration of the dominant frequency as well as a slowing of the centroid of the combined delta/theta band. The total centroid tended towards acceleration, while the centroid deviation increased significantly. These alterations reflect vigilance changes of the dissociative type and differ from those of the classical nootropics. Clinical and psychometric evaluations demonstrated changes in the same direction as in the total sample, but interdrug differences were not significant. Thus, EEG brain mapping seems to be more sensitive in objectivating central drug effects. The aim was to evaluate the efficacy, safety and tolerability of rivastigmine capsules in patients diagnosed with probable vascular dementia (VaD).
                VantagE (Vascular Dementia trial studying Exelon) was a 24-week, multicentre, double-blind study. VaD patients aged 50-85 years were randomized to rivastigmine capsules (3-12 mg/day) or placebo. Efficacy assessments included global and cognitive performances, activities of daily living and neuropsychiatric symptoms. Adverse events were recorded. Additional exploratory analyses determined whether heterogeneity in pathologies and symptoms extended to differential treatment effects.
                NCT00099216.
                710 patients were randomized. Rivastigmine demonstrated superiority over placebo on three measures of cognitive performance (Vascular Dementia Assessment Scale, Alzheimer's Disease Assessment Scale cognitive subscale, Mini-Mental State Examination; all p< or = 0.05, intent-to-treat population [ITT]), but not other outcomes. Predominant adverse events were nausea and vomiting. Exploratory analyses indicated that older patients (> or =75 years old), assumed more likely to also have Alzheimer's disease (AD) pathology, demonstrated significant cognitive responses to rivastigmine and a safety profile similar to that seen in AD patients. Younger patients, assumed less likely to have concomitant AD pathology, showed no efficacy response and were associated with slight elevations of blood pressure, cerebrovascular accidents and mortality. Rivastigmine-placebo differences in patients with, versus those without, medial temporal atrophy (also suggestive of concomitant AD) showed a numerical difference similar to that seen between the older versus younger patients, but did not attain statistical significance.
                Consistent with trials evaluating other cholinesterase inhibitors, rivastigmine did not provide consistent efficacy in probable VaD. The efficacy apparent on cognitive outcomes was derived from effects in older patients likely to have concomitant Alzheimer pathology. This is supportive of an existing argument that the putative cholinergic deficit in VaD reflects the presence of concomitant Alzheimer pathology. There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety of atorvastatin in patients with mild to moderate AD.
                This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13-25), were aged 50-90 years, and were taking donepezil 10 mg daily for > or 3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were > 95 and < 195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global function (Alzheimer's Disease Cooperative Study Clinical Global Impression of Change [ADCS-CGIC]) at 72 weeks.
                A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated.
                In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events. Classification of evidence: This study provides Class II evidence that intensive lipid lowering with atorvastatin 80 mg/day in patients with mild to moderate probable Alzheimer disease (aged 50-90), taking donepezil, with low-density lipoprotein cholesterol levels between 95 and 195 mg/dL over 72 weeks does not benefit cognition (as measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale) (p = 0.26) or global function (as measured by Alzheimer's Disease Cooperative Study Clinical Global Impression of Change) (p = 0.73) compared with placebo.
There is limited evidence that propentofylline might benefit cognition, global function and activities of daily living of people with Alzheimer's disease and/or vascular dementia. The meta-analyses reported here are far from satisfactory as a summary of the efficacy of propentofylline, considering the unpublished information on another 1200 patients in randomized trials that exists. Unfortunately Aventis has been unwilling to correspond with the authors, significantly limiting the scope of this review.