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Results
Patient Disposition
Patient disposition has been described previously. Briefly, 701 subjects were screened for eligibility, 302 were excluded and 399 were randomized. Subjects were well matched for demographic characteristics with no significant differences between groups (Table 1).
On-treatment Analysis
Statistical analysis on ADAS-cog was performed using all available on-treatment data. Beginning with Month 3, there were 127 subjects in the placebo group and 126 subjects in the 5 mg/day dose group with baseline and on-treatment data. Mean changes and median changes in ADAS-cog are consistent in showing numerical active-placebo differences favoring the 5 mg/day dose group over time. (Table 2, Figure 1, panel B) At all time points, the numerical difference favors the 5 mg/day dose group over placebo, with nominal significance at Month 18 (Δ=2.7, p = 0.03).
Exploratory Analysis by Disease Severity
Analysis was performed on the FAS (ITT) comparing ADAS-cog and CDR-sb in patients with mild AD (MMSE ≥20) and moderate AD (MMSE < 20)). For ADAS-cog, a 3.3 point (p = 0.024) and 2.7 point (p = 0.4) difference between 5 mg/day and placebo was seen at Month 18 in the mild group and moderate group, respectively. For CDR-sb , a 0.72 point (p = 0.053) and 0.74 point (p = 0.5) difference between 5 mg/day and placebo was seen at Month 18 in the mild group and moderate group, respectively. These findings were confirmed in post-hoc subgroup analyses defining mild patients as having baseline ADAS-cog ≤19 (n = 25 in each treatment group, observed cases at 18 months). These analyses reveal a delta at 18 months, favoring 5 mg/day over placebo, on ADAS-cog of 5.9 points (p < 0.01) and trends on CDR-sb (delta = 1, p = 0.08) and ADCS-ADL (delta = 4.92, p = 0.07) (Figure 2). The beneficial effect of 5 mg/day in patients with moderate AD (ADAS-cog >19) was less pronounced with a delta (5 mg/day vs. placebo) at 18 months of 1.45 for ADAS-cog, 0.74 for CDR-sb, and 0.57 for ADCS-ADL.
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Figure 2.
Estimated mean change from baseline over time on ADAS-cog 11, CDR-sb and ADCS-ADL for patients with mild Alzheimer's disease defined as either MMSE ≥20 (Panels A, B and C) or ADAS-cog ≤19 (Panels D, E, F) at baseline. Error bars represent one standard error. (A) ADAS-cog treatment-placebo difference at 18 months = 3.3, p = 0.024, Baseline MMSE ≥ 20; (B) CDR-sb treatment-placebo difference at 18 months = 0.72, p = 0.053, Baseline MMSE ≥ 20; (C) ADCS-ADL treatment – placebo difference at 18 months = 2.2, p = 0. 3, Baseline MMSE ≥ 20 (D) ADAS-cog treatment-placebo difference at 18 months = 5.9, p < 0.008, Baseline ADAS-cog ≤ 19; (E) CDR-sb treatment-placebo difference at 18 months = 1, p = 0.08, Baseline ADAS-cog ≤ 19; (F) ADCS-ADL treatment-placebo difference at 18 months = 4.92, p = 0.07, Baseline ADAS-cog ≤ 19.
TTP488 Plasma Concentration Driven Analysis
As expected, higher plasma TTP488 trough concentrations (mean, median of trough concentrations over the study duration, mean of trough concentrations over study duration) were observed for 20 mg/day, and lower concentrations observed for 5 mg/day (Table 3, Figure 3).
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Figure 3.
TTP488 plasma concentration over time. On-treatment data where on-treatment is defined as plasma concentrations measured within 45 days of last administered dose. Data presented as mean values with 95% confidence boundary. For the 20 mg/day group data presented through Month 15 after which there were too few observations.
Within certain concentration ranges, delineation from placebo in changes in ADAS-cog was more pronounced than in other ranges (Table 4). Subjects with concentrations in the lowest 20% (0.1–10.2 ng/mL) and second lowest 20% (10.3–16.8 ng/mL) showed benefit over placebo at 18 months. The effect in the 0.1–10.2 ng/mL group was primarily driven by those subjects with concentrations greater than 7.6 ng/mL. Subjects in the middle 20% group (17.0–46.3 ng/mL) showed similar effects as placebo. Subjects in the top two groups (46.8–71.7 ng/mL and 74.0–167.0 ng/mL) showed a numerical worsening in ADAS-cog relative to placebo through 12 months after which time the number of subjects in these quintiles is too few to allow for meaningful interpretations.
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