However, it is also possible that there may be a ceiling effect for the cholinergic mechanism or that insufficient acetylcholine remains at the synapses in mild-to-moderate AD patients to allow a modulator the opportunity to achieve its effect, in which case different results could theoretically be observed in patients at an earlier stage of the disease. Discussion MK-7622 (45?mg) does not improve cognition or function when used as adjunctive therapy in mild-to-moderate Alzheimer’s disease. value was provided for the between-group comparison using the Miettinen and Nurminen method. All statistical analyses were performed using SAS, version 9.3 (SAS Institute, Cary, NC, USA). The trial planned to randomize 250 participants into MK-7622 45?mg and placebo groups (1:1 ratio). The sample size of 125 participants per group provided 80% power to declare that MK-7622 45?mg was superior JD-5037 to placebo on the primary endpoint, if the underlying treatment difference in mean changes from baseline in ADAS-Cog11 score was two points. The power and sample size were based on an expected dropout rate of approximately 8% by week?12. Interim analyses were conducted for safety (after 60 participants had reached 8?weeks) and for futility (after 188 participants had reached 12?weeks) and were reviewed by a data-monitoring committee comprised of Merck researchers who were not otherwise involved in the study. Criteria were set to conclude futility if the conditional power of observing a significant difference on the 12-week ADAS-Cog11 was less than 20%. 3.?Results 3.1. Patient disposition A total of 240 participants were randomized, and 239 received at least one dose of study treatment (Fig.?1). The trial was stopped for futility after meeting the prospectively defined stopping threshold. At the time of study termination, 144 participants had completed the study. The majority of discontinuations were due to the early study termination. Open in a separate window Fig.?1 Study flowchart. aN?=?number analyzed for the primary endpoint of ADAS-Cog11 at week 12. Abbreviation: ADAS-Cog, Alzheimer’s Disease Assessment ScaleCCognitive Subscale. Characteristics of treated participants are shown in Table?1. Overall, the participant characteristics were consistent with the targeted mild-to-moderate AD population, and demographics were well balanced between treatment groups. Table?1 Characteristics of treated participants genotype?Negative46 (38.7)55 (45.8)?Positive73 (61.3)65 (54.2)AD severity by MMSE score?12C18 (moderate)63 (52.9)65 (54.2)?19C24 (mild)56 (47.1)55 (45.8)Time of initial AD diagnosis? 6?months ago9 (7.6)7 (5.8)?6C12?months45 (37.8)37 (30.8)? 24?months65 (54.6)76 (63.3)Use of memantine at JD-5037 screening?No70 (58.8)58 (48.3)?Yes49 (41.2)62 (51.7)Prior AD medication?Donepezil103 (86.6)104 (86.7)?Other AchEI16 (13.4)16 (13.3) Open in a separate window Abbreviations: APOE4, apolipoprotein E -4; AD, Alzheimer’s disease; MMSE, mini mental state examination; AchEI, acetylcholinesterase inhibitors; SD, standard deviation. NOTE. Data are represented as number (%) of participants, except for mean (SD) age. 3.2. Efficacy Efficacy findings are summarized in Table?2. Participants treated with MK-7622 45?mg, as compared with those treated with placebo, did not show statistically significant improvement Rabbit Polyclonal to MCL1 on the primary endpoint of the ADAS-Cog11 at week 12 (change from baseline?=?0.18 points; 95% confidence interval: ?1.00 to 1 1.37; value?=?.762). No treatment differences on the ADAS-Cog11 were observed at other time points (Fig.?2) or in subgroups (Fig.?3). MK-7622 did not significantly improve function as assessed by the secondary endpoint of Alzheimer’s Disease Cooperative StudyCActivities of Daily Living Inventory score at week 24 or at week 12 (Fig.?4). No treatment differences were seen on other endpoints (Table?2). Sensitivity analyses performed using an intent-to-treat population for the efficacy endpoints did not show meaningfully different findings from the primary approach (data not shown). Table?2 Efficacy results JD-5037 at weeks 12 and 24 genotype (positive, negative), AD medication stratum (donepezil, other acetylcholinesterase inhibitors), gender, the use of memantine (use, no use), the time-by-treatment interaction, and age as continuous covariate. Open in a separate window Fig.?2 ADAS-Cog11 mean (SE) change from baseline scores over JD-5037 24?weeks (a negative score indicates improvement, JD-5037 and a positive score indicates worsening relative to baseline); dashed line?=?MK-7622 and solid line?=?placebo. Abbreviations: ADAS-Cog, Alzheimer’s Disease Assessment ScaleCCognitive Subscale; SE, standard error. Open in a separate window Fig.?3 Estimated difference (95% CI) versus placebo in change from baseline ADAS-Cog11 score by subgroups (a negative score indicates improvement, and a positive score indicates worsening relative to baseline). Abbreviations: APOE4, apolipoprotein E -4; ADAS-Cog, Alzheimer’s Disease Assessment ScaleCCognitive Subscale; AchEIs, acetylcholinesterase inhibitors; CI, confidence interval. Open in a separate window Fig.?4 ADCS-ADL mean (SE) change from baseline scores at week 12 and 24 (a negative score indicates worsening relative to baseline); dashed line?=?MK-7622 and solid line?=?placebo. Abbreviations: ADCS-ADL, Alzheimer’s Disease Cooperative StudyCActivities of Daily Living Inventory; SE, standard error. 3.3. Safety Adverse events are summarized in Table?3. There were no deaths. Although not statistically significant (i.e., the 95% confidence.
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