Double-blind placebo-controlled study of velnacrine in Alzheimer's disease. Velnacrine for the treatment of Alzheimer's disease: a double-blind, placebo-controlled trial. The Mentane Study Group. Effectiveness and safety of velnacrine for the treatment of Alzheimer's disease. A double-blind, placebo-controlled study. Mentane Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment.
The present study assessed the safety and efficacy of the cholinesterase inhibitor, velnacrine, for treating the cognitive symptoms of Alzheimer's disease. Patients (N = 236) meeting NINCDS-ADRDA criteria for Alzheimer's disease entered a double-blind, placebo-controlled dose-ranging protocol (30, 75, 150, 225 mg/day each for one week) to identify velnacrine responders (> or = four point improvement on the cognitive subscale of the Alzheimer's Disease Assessment Scale [ADAScog]). After a two week drug washout, velnacrine responders were randomly assigned to their best velnacrine dose or placebo in a six week dose-replication protocol employing the ADAScog and the Clinical Global Improvement scale as primary outcome measures. During dose-replication, intent-to-treat analysis revealed that velnacrine patients scored significantly better than placebo patients on the ADAScog after two (p < 0.004), four (p < 0.025) and six (p < 0.001) weeks of treatment. No significant treatment effect on Clinical Global Improvement scores was observed. The primary adverse event was an asymptomatic elevation of liver transaminases found among 28% of the 236 treated patients. Cholinergic side effects including diarrhea (14%), nausea (11%) and vomiting (5%) were observed and 8% of patients experienced skin rash. The present study identified a subgroup of Alzheimer's patients who demonstrated a significant, but modest, improvement during velnacrine treatment on structured cognitive testing. The present study examines the safety and efficacy of the centrally acting cholinesterase inhibitor, velnacrine, in treating the cognitive symptoms of Alzheimer's disease. Seven hundred thirty-five patients with mild-to-severe Alzheimer's disease were treated in a double-blind, placebo-controlled study. Following the screen visit, patients were treated with velnacrine (10, 25, 50 and 75 mg t.i.d.) or placebo in a double-blind dose-ranging study to identify velnacrine-responsive patients and their best dose. Following placebo washout velnacrine responsive patients were randomly assigned to their best dose of velnacrine (N = 153) or placebo (N = 156) in a six week double-blind dose-replication study. Primary efficacy measures were the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS) and the Physician's Clinical Global Impression of Change. Statistically significant improvement was observed in both primary efficacy measures in velnacrine-treated patients during the dose-replication study. Velnacrine patients scored better on the cognitive subscale of the ADAS than placebo patients (P < 0.001), with patients receiving the highest velnacrine dose averaging a 4.1-point improvement with respect to screen values. Clinical Global Impression of Change scores of velnacrine-treated patients were significantly improved at the end of the 6 weeks of treatment when compared to those of placebo patients (P < 0.05). The most common side effect was asymptomatic elevation in liver transaminase levels, which occurred among 29% of patients. These data suggest that velnacrine produces modest clinical improvement in a subset of patients with mild-to-severe Alzheimer's disease. Alzheimer's disease is characterized by cognitive and behavioral disturbances that are mediated in part by cholinergic brain deficits.
                To evaluate the long-term effectiveness and safety of an investigational cholinesterase inhibitor, that is, velnacrine maleate, in treating patients with clinically probable Alzheimer's disease (according to the criteria of the National Institute of Neurological Disorders and Stroke [Washington, DC]-Alzheimer Disease and Related Disorders Association [Chicago, Ill]).
                This was a double-blind, placebo-controlled study. After a single-blind washout period, patients were randomized to receive placebo (n = 152), velnacrine maleate, 150 mg/d (n = 149), or velnacrine maleate, 225 mg/d (n = 148) for 24 weeks. Primary end points were cognitive behavior and memory components of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale. Secondary end points were caregiver-rated scales.
                The scores for the cognitive behavior and memory components of the Alzheimer's Disease Assessment Scale deteriorated in the placebo-treated group (P < .05) but not in the velnacrine-treated groups. Between-group comparisons favored velnacrine maleate, 225 mg over 150 mg (P < .05). Findings were similar for the Clinical Global Impression of Change scale and three of the four caregiver-rated scales. Treatment-related adverse clinical events occurred in 36%, 28%, and 30% of patients in the groups that received placebo, velnacrine maleate (150 mg), and velnacrine maleate (225 mg), respectively. The most common adverse clinical event was diarrhea, which rarely interrupted therapy. Treatment was stopped because of reversible abnormal liver function test results (five or more times the upper limits of normal) in 3%, 30%, and 24% of the patients who received placebo, velnacrine maleate (150 mg), and velnacrine maleate (225 mg), respectively.
                Velnacrine produces modest but significant benefits in patients with Alzheimer's disease. Velnacrine maleate (225 mg) is more effective than 150 mg of velnacrine. Both dosages have acceptable safety profiles. Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer's disease.
                In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer's disease; secondary outcomes were cognition and function.
                A total of 769 subjects were enrolled, and possible or probable Alzheimer's disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer's disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer's disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer's disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E epsilon4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer's disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E epsilon4 carriers.
                Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, the rate of progression to Alzheimer's disease after three years was not lower among patients treated with donepezil than among those given placebo.
                Copyright 2005 Massachusetts Medical Society.
There has been no research into the use of velnacrine as a cognitive enhancer in the treatment of Alzheimer's disease since 1994. The FDA peripheral and CNS drug advisory board voted unanimously against recommending approval. This review shows the toxic nature of velnacrine, and provides no evidence of efficacy. There are no grounds for further research into velnacrine.