Table 2.
Change in Primary and Secondary Outcomes from Baseline to Week 104.*
| Outcome | Change from Baseline (95% Cl) | Difference in Mean Change | |||||
|---|---|---|---|---|---|---|---|
| Verubecestat 12 mg |
Verubecestat 40 mg |
Placebo | Verubecestat 12 mg vs. Placebo (97.51% Cl or 95%CI)† |
P Value ‡ | Verubecestat 40 mg vs. Placebo (97.51% Cl or 95%CI)† |
P Value ‡ | |
| Primary outcome | |||||||
| CDR-SB score | 1.65 (1.42 to 1.87) | 2.02 (1.75 to 2.28) | 1.58 (1.34 to 1.81) | 0.07 (−0.30 to 0.44) | 0.67 | 0.44 (0.04 to 0.84) | 0.01 |
| Secondary outcomes | |||||||
| Progression to dementia — no. of events/ 100 patient-yr§ |
24.5 | 25.5 | 19.3 | — | — | — | — |
| Change in CDR-SB score wk 13 to wk 104 |
— | — | — | 0.0 (−0.3 to 0.4) | 0.3 (−0.1 to 0.7) | ||
| CCS-3D score | 0.77 (0.66 to 0.87) | 0.78 (0.66 to 0.89) | 0.77 (0.65 to 0.89) | 0.00 (−0.18 to 0.17) | 0.01 (−0.18 to 0.20) | ||
| Hippocampal volume on MRI — % change¶ |
−6.5 (−6.9 to −6.2) | −6.7 (−7.1 to−6.3) | −6.1 (−6.5 to−5.7) | −0.4 (−1.0 to 0.2) | −0.6 (−1.2 to 0.0) | ||
| Cortical amyloid load on PET —SUVR¶ |
−0.03 (−0.04 to −0.03) | −0.04 (−0.05 to −0.04) | 0.02 (0.02 to 0.03) | −0.05 (−0.06 to −0.04) | −0.06 (−0.07 to −0.05) | ||
| ADCS-ADLMCI score | −5.2 (−6.1 to−4.3) | −5.8 (−6.8 to −4.8) | −4.1 (−5.0 to−3.3) | −1.0 (−2.4 to 0.4) | −1.7 (−3.2 to−0.2) | ||
| Total tau in CSF | NA | NA | NA | NA | NA | ||
| Exploratory outcomes | |||||||
| ADAS-cog13 score | 8.0 (7.2 to 8.9) | 8.2 (7.3 to 9.1) | 6.9 (6.1 to 7.7) | 1.1 (−0.1 to 2.3) | 1.3 (0.1 to 2.6) | ||
| ADAS-cog11 score | 6.3 (5.5 to 7.0) | 6.5 (5.7 to 7.3) | 5.2 (4.5 to 5.9) | 1.1 (0.1 to 2.1) | 1.3 (0.2 to 2.3) | ||
| MMSE score | −3.8 (−4.2 to−3.4) | −4.7 (−5.3 to−4.2) | −3.9 (−4.4 to −3.5) | 0.1 (−0.5 to 0.8) | −0.8 (−1.5 to−0.1) | ||
| NPI score | 2.7 (1.4 to 3.9) | 3.5 (2.1 to 4.8) | 1.5 (0.5 to 2.5) | 1.1 (−0.5 to 2.7) | 1.9 (0.2 to 3.6) | ||
Values shown are least-squares means with confidence intervals, with the exception of progression to dementia, for which the numbers of events per 100 patient-years are shown. All analyses except progression to dementia due to Alzheimer’s disease are based on longitudinal analysis of covariance with categorical factors of geographic region, time, trial-group assignment, sex, APOE4 genotype, baseline use of Alzheimer’s disease medication, baseline use of vitamin E, and the interaction of time according to trial-group assignment with baseline value, the interaction of baseline value and time, the baseline value ofthe MMSE score, and the baseline value of age included as continuous covariates. For CDR-SB, CCS-3D, ADAS-cog, and NPI, a higher positive mean change-from-baseline score corresponds to a greater decline relative to baseline, and a positive treatment difference indicates a greater decline with verubecestat than with placebo. For ADCS-ADLmci and MMSE, a higher negative mean change-from-baseline score corresponds to a greater decline relative to baseline, and a negative treatment difference indicates a greater decline with verubecestat than with placebo. For the change in CDR-SB score from week 13 to week 104, a positive treatment difference indicates a greater worsening at week 104 than at week 13 with verubecestat than with placebo. Progression to dementia due to Alzheimer’s disease is based on a Cox pro-portional-hazards model with adjustment for APOE4 genotype, sex, geographic region, baseline use of medication for Alzheimer’s disease, and baseline use of vitamin E as categorical terms, with baseline age and baseline MMSE score as continuous covariates. A higher change-from-baseline score corresponds to more events (greater decline) relative to baseline. CSF denotes cerebrospinal fluid, and NA not applicable.
The 97.51% confidence intervals are presented for primary and secondary outcomes, and the 95% confidence intervals are presented for exploratory outcomes (unadjusted for multiple comparisons).
P values for the primary outcome are two-sided. According to the strategy of adjustment for multiple testing, the primary hypothesis that verubecestat is superior to placebo with respect to the change from baseline in the CDR-SB score was not supported at either dose level; thus, further formal hypothesis testing was precluded.
In the category of progression to dementia due to Alzheimer’s disease, the hazard ratio for 12 mg vs. placebo was 1.30 (1.01 to 1.68), and the hazard ratio for 40 mg vs. placebo was 1.38 (1.07 to 1.79). A hazard ratio greater than 1 indicates more events (greater decline) with verubecestat than with placebo.
These analyses were based on smaller or substantially smaller sample sizes than the analyses for the clinical outcome scales. For biomarkers, a negative mean change corresponds to a reduction in the biomarker value relative to baseline and a positive mean change indicates an increase in the biomarker value relative to baseline.