Bridging Study of S12024 in 53 In‐patients With Alzheimer's Disease

To the Editor: S12024 is a new compound potentially useful for Alzheimer's Disease (AD). Cognition-enhancing properties have been demonstrated, in animals, on memory function, acquisition, and recall.1,2 S12024 increases noradrenergic, vasopressinergic, and nicotinic neurotransmissions.3 The clinical and biological tolerance of the compound has been studied extensively in Phase I studies, up to 600 mg in young healthy volunteers and up to 400 mg/day as multiple oral doses in healthy older volunteers. A beneficial effect on memory components in older volunteers was detected at both 100 and 200 mg/day.4 The present study describes the first data on the use of S12024 in older patients diagnosed as AD. The objectives of this typical bridging study were to assess preliminary evidence of cognitive effects, safety, and dose/effects relationship of a 1-month treatment with S12024 in moderate to severe (MMS between 10 and 23), old (age range: 75–90 years) in-patients with AD according to NINCDS-ADRDA, DSM-III-R, Hachinsky score, CT-scan, criteria, and requirements. The trial was designed as a multicenter, double-blind randomized, parallel group comparison of three dosages of S12024 (100; 200; 400 mg once daily) and placebo. The total duration of the study was 8 weeks, including a placebo run-in period (2 weeks), a double-blind treatment period (4 weeks), and a follow-up phase (2 weeks). Safety was assessed daily through a clinical global impression scale (CGI) and clinical testing; main biological and vital parameters were measured at baseline and then on days (D) 14 and 28. Psychomotor and cognitive performances were assessed at baseline, D14, and D28 through the use of computerized batteries of tests, CDR,5 and scores of Memory SM56 according to a methodology we recently summarized.7 Data were analyzed on an intention-to-treat basis for all safety parameters. Fisher's test and Cochran-Mantel-Haenszel-test were used to analyze activity results. A total of 53 patients (14 subjects in the 100 mg group, 13 in the three other groups) were randomized (mean age 80.7 + 1; 21% men), with a baseline homogeneity in the four treatments for the demographic and disease characteristics (i.e., MMS between 16.5 and 18). Eleven patients (21%) discontinued the treatment because of adverse events (onset between D3 and D16). These drug-associated transient and regressive events were mainly digestive (anorexia, nausea, vomiting) and central nervous system effects (headache, vertigo). Three cases of gart instability were reported, possibly related to the two highest dosages. No significant changes were shown for vital signs, EKG, and biology in all treatment groups. As usual in such designs, the global scales (MMS, CGI) did not show any change. On the other hand, statistically significant improvements or trends were obtained for the compound on the objective measurements. Beneficial effects were the most frequent and the most coherent in the 200-mg group. In the CDR battery, choice reaction times, vigilance speed, and combined memory index were statistically significantly improved at D14 (P < .02), and trends were noticed for speed of attention performance (P = .07), recognition tasks (P = .07), and attention performance in the combined attentional tasks (P = .07). In the SM5 battery, trends supporting 200 mg were also observed at D28 on word-recognition task (P = .07), words recall task, and false-face recognition task at D14 (P = .06). S12024 appears to have a good safety profile on this very old and frail demented population. A dose dependency of adverse events has been determined. The 200 mg/day dosage appears to give the optimal index of activity on the quality and the performance of memory. Those results were further confirmed in larges scale controlled phase II studies.8 The present research confirms that bridging studies are critical in antidementia drug development and can optimize the next steps of development in the treatment of AD.