Participants
Between May 19, 2015 and January 26, 2018, ninety-six participants were screened, of whom fifty were randomized to the treatment of either rasagiline or matching placebo and forty-three completed treatment. Of the twenty-five participants allocated to the placebo arm, three were lost to follow up (associated with delusions (1), stroke (1), and worsening pseudobulbar/other effects (1, discontinued at baseline)), and one participant did not have a week-24 FDG PET scan but had clinical data, resulting in twenty-one placebo participants for image analysis. Of the twenty-five participants allocated to the rasagiline arm, four were lost to follow-up (associated with broken hip/rib (1), atrial fibrillation (1), and factors other than adverse events (2)). (Fig. 1. Trial profile)
Table 1 shows the demographic and baseline clinical characteristics of the enrolled patients by study arm. Age, sex, education, genotype, and baseline NPI, DSPAN, and COWAT scores did not differ between groups. Ninety-four percent of participants were Caucasian (non-Hispanic). Mean MMSE and ADAS-cog scores at baseline were more impaired in the placebo group than the rasagiline group (p < 0·06), while the rasagiline group had worse baseline QoL-AD scores (p < 0·02). Baseline values were included as covariates in statistical comparisons of longitudinal change for these endpoints. Pre-specified subgroup analyses stratified by baseline MMSE were also performed. Of the forty-three participants who completed the study, one did not have a week-24 FDG PET scan and three were excluded from longitudinal image analysis due to pre-specified behavioral or motion confounds during image acquisition. Among the thirty-nine participants included in longitudinal image analysis, baseline MMSE and ADAS-cog scores did not differ between groups and QoL-AD scores were lower (worse) in the rasagiline-treated group (p < 0·05).
Table 1
Baseline demographic and clinical characteristics of the study population
| Placebo (N = 25) | Rasagiline (N = 25) | All (N = 50) | p-value (Placebo vs. Rasagiline) |
Age (range) | 73.4 (7.1) (57–84) | 74.7 (7.4) (62–90) | 74 (7.2) (57–90) | 0.53 |
Gender (F/M)% | 44 / 56 | 56 / 44 | 50 / 50 | 0.60 |
Education | 14 (2) | 14 (3 | 14 (3) | 0.83 |
ADAS-Cog | 28 (11) | 23 (6) | 26 (9) | 0.055 |
MMSE | 19 (5) | 21 (4) | 20 (4) | 0.064 |
ADL | 58 (11) | 62 (8) | 60 (10) | 0.20 |
NPI | 8 (9) | 8 (8) | 8 (8) | 0.78 |
DSPAN | 12 (3) | 13 (3) | 12 (3) | 0.13 |
COWAT | 21 (13) | 27 (13) | 24 (13) | 0.13 |
QOL-AD | 40 (5) | 36 (6) | 38 (6) | 0.018 |
APOE 2/3 | 4% | 4% | 4% | 0.50 |
2/4 | 0% | 4% | 2% | |
3/3 | 16% | 29% | 22% | |
3/4 | 60% | 38% | 49% | |
4/4 | 20% | 25% | 22% | |
AChEI(s) | 84% | 84% | 84% | 1.0 |
Memantine | 44% | 40% | 42% | 0.78 |
Antidepressant(s) | 36% | 56% | 46% | 0.16 |
Anxiolytic(s) | 4% | 4% | 4% | 1.0 |
Antipsychotic(s) | 8% | 4% | 6% | 0.56 |
site id 1 | 48% | 52% | 50% | 1.0 |
site id 2 | 36% | 36% | 36% | |
site id 3 | 16% | 12% | 14% | |
Baseline PET and ApoE Characterization
Of the fifty-nine participants who had screening FDG scans analyzed using the Dementia Classifier, fifty-seven exhibited a pattern of hypometabolism classified as AD-like and were included for potential enrollment. Seventy-one percent of participants were ApoE-4 carriers, consistent with trials where positive amyloid imaging is used as an entry criterion29. Participants were diverse in FDG AD Progression Classifier scores (Fig. 2a), which correlated with the range of baseline MMSE (R = -0.44, p < 0.001, Fig. 2d) and ADAS-cog scores (R = 0.42, p < 0.003). AD Progression score and baseline MMSE did not differ significantly between study arms in the PET analysis population. Younger participants had lower metabolism in inferior parietal (p < 0.008) and precuneus (p < 0.04) regions as compared to older participants at baseline.
Total tau burden varied greatly across participants (Figs. 2b,c,d) but did not differ between study arms. Tau was associated with age (Fig. 2e); younger participants (age 57 to 69) had pervasive tau distribution inclusive of frontal and parietal cortices while oldest participants (late 70 s to 90) had low total burden consisting primarily of temporal tau with smaller posterior clusters. Participants in their 70 s showed a broad range from low to moderate total tau. Spatial patterns varied, with hemispheric asymmetries in some participants and a dominant occipital burden observed in several participants. Forty-seven of the fifty participants enrolled in the study had readily visualized elevated flortaucipir signal and positive regional SUVRs. Three (of whom two completed the study) had threshold cortical SUVR values (1.3). Total tau burden correlated with FDG AD Progression classifier score (R = -0.41, p < 0.003).
Trial Outcomes
Primary end point
The study met its primary endpoint of improvement in longitudinal glucose metabolism in rasagiline-treated participants versus those on placebo in one or more prespecified regions (Fig. 3a). Table 2 shows percentage changes and the SUVR values, which were used for the statistical comparisons. Rasagiline-treated participants decreased to a lesser magnitude than placebo-treated participants in the pre-specified regions of middle frontal cortex (left p < 0.012, E.S. 0.82; bilateral p < 0.025, E.S. 0.75), anterior cingulate cortex (p < 0.043, E.S. 0.68), striatum (p < 0.02, E.S. 0.83), and in superior frontal cortex (p < 0.05, not pre-specified). Results using whole brain, subcortical white matter, and pons as alternate reference regions were in agreement regarding affected regions and directionality.
A voxel-based classifier comparison of change in placebo- and rasagiline-treated groups (an additional primary outcome measure) identified a spatial pattern in which rasagiline-treated participants had lesser decline in glucose metabolism than those on placebo (p < 0.02). This pattern, illustrated in Fig. 3b, is consistent with the pre-specified region of interest results and includes middle frontal, anterior cingulate, superior frontal, striatal, and insular regions, and less prominently, inferior parietal cortex.
Table 2
Region of interest results: Difference (24 weeks minus baseline) Mean, S.D. and Difference between Arms with 95% Confidence Interval
| Middle Frontal | Anterior Cingulate | Superior Frontal | Striatum | Medial Temporal | Lateral Temporal | Post Cing - Precuneus | Inferior Parietal |
SUVRs |
Placebo | -0.032 (0.030) | -0.020 (0.021) | -0.016 (0.022) | -0.024 (0.029) | -0.015 (0.034) | -0.020 (0.029) | -0.017 (0.023) | -0.025 (0.029) |
Rasagiline | -0.011 (0.030) | -0.003 (0.026) | -0.003 (0.018) | -0.002 (0.028) | -0.010 (0.034) | -0.016 (0.024) | -0.016 (0.018) | -0.018 (0.022) |
Difference (95% CI) | 0.020 (0.00–0.04) | 0.016 (-0.00–0.03) | 0.013 (0.00–0.04) | 0.022 (0.00–0.04) | 0.005 (-0.02–0.03) | 0.005 (-0.01–0.02) | -0.001 (-0.01–0.01) | 0.007 (-0.01–0.02) |
Percentages |
Placebo | -3.5% | -2.8% | -2.0% | -2.6% | -2.5% | -2.7% | -2.2% | -2.6% |
(3.5%) | (3.1%) | (2.7%) | (3.1%) | (5.7%) | (4.4%) | (3.1%) | (3.5%) |
Rasagiline | -1.0% | -0.6% | -0.4% | -0.2% | -1.8% | -2.1% | -2.0% | -1.6% |
(3.5%) | (3.1%) | (2.1%) | (3.1%) | (5.7%) | (4.4%) | (3.1%) | (3.5%) |
Difference (95% CI) | 2.5% (0.3–4.7%) | 2.2% (0.1–4.3%) | 1.6% (0.0·3.2%) | 2.4% (0.2·4.3%) | 0.8% (-2.4·4.0%) | 0.6% (-1.8–3.0%) | 0.2% (-1.5–1.9%) | 0.9% (-1.5–3.3%) |
p-values* | 0.025 | 0.041 | 0.054 | 0.023 | n.s. | n.s. | n.s. | n.s. |
*based on the SUVR values and comparison of differences from baseline; n.s. = not significant |
The decline in glucose metabolism in the placebo arm was consistent with expected changes in severity of AD over the 24-week period. FDG AD Progression scores increased in severity (p < 0.01 at 80% power), and regional SUVRs decreased in posterior cingulate-precuneus (p < 0.03, E.S. 0.74), inferior parietal (p < 0.01, E.S. 0.86), and middle frontal (p < 0.001, E.S. 1.74) (p-values at 80% power) regions consistent with the change in Progression scores. Mean decreases in glucose metabolism in younger placebo-treated participants were more than twice those of older placebo-treated participants in middle frontal (p < 0.07, left p < 0.05) and caudate (p < 0.05) regions.
Secondary Endpoints
Longitudinal clinical endpoints for the rasagiline and placebo treatment arms over 24 weeks showed a favorable outcome for the rasagiline group compared to the placebo group for QoL-AD (p < 0.04), with directional trends on COWAT (p < 0.08) and MMSE (p < 0.07) (Table 3). Results suggested that clinical endpoint differences at baseline, included as covariates in the statistical models and tested for impact in additional subanalyses, did not impact longitudinal comparisons between arms. There were no significant site effects.
In the pre-specified moderate subgroup (MMSE 10 to 18, N = 14), rasagiline-treated participants showed less decline than placebo treated participants in 6 of 8 clinical endpoints, at trend level in QoL-AD (p < 0.06) and COWAT (p < 0.09);. In the pre-specified mild subgroup (baseline MMSE 19 to 28, N = 36), rasagiline-treated participants had less decline, not significant, in 5 of 8 clinical endpoints (results in Table 3).
Table 3
Clinical endpoint longitudinal results
Endpoint | 24 week mean change (S.D.) | p-value |
Placebo | Rasagiline | |
MMSE | 1.14 (2.27) | 0.65 (2.48) | n.s. |
ADAS-cog | 2.76 (4.30) | 1.81 (4.43) | n.s. |
ADL | 3.23 (6.71) | 3.75 (7.27) | n.s. |
COWAT | 1.09 (6.31) | -0.62 (5.55) | 0.08 |
CGIC | n/a | n/a | n.s. |
Digit Span | 1.18 (1.92) | 0.29 (3.08) | n.s. |
NPI | 2.00 (7.18) | 0.20 (6.79) | n.s. |
QoL-AD | 1·95 (3·28) | -1·11 (3·77) | 0.04 |
S.D. = standard deviation; Mod = moderate; n.s. = non-significant |
Relationships between baseline imaging characteristics and changes in clinical endpoints
Higher tau burden, lower glucose metabolism, and lower cortical thickness in temporal regions at baseline correlated with greater decline in MMSE score in placebo treated participants (blue line) over the 24-week period (p < 0.008, p < 0.05, and p < 0.004 respectively). These relationships, shown in Fig. 5a, were not seen in the rasagiline trajectories (red lines), which were relatively stable or improved independent of their tau burden, glucose metabolism, or cortical thickness values at baseline. Longitudinal differences between the rasagiline and placebo arms were most pronounced in participants having greater tau, lower metabolism, and lower volumes in temporal regions at baseline.
Relationships between change in clinical endpoints and change in imaging biomarkers
The metabolic pattern resulting from the voxel-based classifier relating change in QoL-AD to changes in FDG PET showed increases (or mitigated decreases) in anterior cingulate, medial orbitofrontal, anterior superior frontal, and caudate regions associated with increasing QoL-AD score (Fig. 5b,c). Consistent with this, QoL-AD score was positively correlated with region of interest FDG SUVR changes in anterior cingulate (R = 0.47, p < 0.002, Fig. 7c) and caudate (R = 0.47, p < 0.002) (Fig. 5d). Longitudinal changes in COWAT and DS were positively correlated with change in middle frontal glucose metabolism (R = 0.52, p < 0.02 and 0.55, p < 0.01, respectively).
Longitudinal Tau PET
Increases in tau (flotaucipir) were observed in some participants over the 24 weeks, particularly in those with higher baseline values (Fig. 6a,b). Greater slopes and statistical power were observed when using the adaptive method that defined the region of interest according to pre- or post- suprathreshold voxels (Fig. 6b).
No differences in the change in flortaucipir were observed between study arms in cortical regions except for slight decreases noted in rasagiline subjects having subthreshold values in anterior cingulate and insula. Uniform longitudinal decreases were observed in the rasagiline arm but not the the placebo arm in the following subcortical regions: accumbens (p < 0.0001), putamen (p < 0.003), thalamus (p < 0.05), brainstem (p < 0.03) (p-values are for the comparison of 24 week flortaucipir SUVR change between rasagiline and placebo arms).
Safety and Tolerability
Rasagiline was generally well tolerated, with neuropsychiatric adverse events (AEs) in 5 (20%) placebo, 0 (0%) rasagiline, non-neuropsychiatric AEs in 10 (40%) placebo patients, 13 (52%) rasagiline, and no treatment-related deaths. Adverse events (AEs) with frequency of > 5% are presented by treatment group in Table 4, with those classified as severe identified in brackets. There were no rasagiline-treated participants who experienced neuropsychiatric symptoms of agitation/irritability or psychosis compared to 5 participants in the placebo group, (t-test NS). As seen in Table 4, there were higher rates of hypertension, increased thyroid stimulating hormone (TSH), falls and skin rashes with rasagiline treatment though treatment arm differences were small and most were not severe. Serious adverse events were observed in two rasagiline treated participants (1 fall, 1 disorientation) as compared to seven placebo treated patients.
Table 4
Adverse Event | Placebo (n = 25) Number Percent | Rasagiline (n = 25) Number Percent |
Abnormal Urinary Analysis | 1 | 4% | 2 | 8% |
Agitation | 2 | 8% | 0 | 0% |
Confusion | 2 | 8% | 2 | 8% |
Delusions | 3 | 12% | 0 | 0% |
Elevated blood pressure or cardiac related | 2 | 8% | 3 | 12% |
Elevated thyroid stimulating hormone | 1 | 4% | 2 | 8% |
Fall | 1 | 4% | 2 | 8% |
Insomnia | 2 | 8% | 0 | 0% |
Rash / skin lesion | 1 | 4% | 2 | 8% |
Number and percent of subjects with adverse events who received 1 or more doses of study drug (occurring in 5% or more in either treatment group).