Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial.

Importance: There are limited efficacious treatments for Alzheimer disease. Objective: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, and Participants: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main Outcomes and Measures: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Results: Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. Conclusions and Relevance: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population. Trial Registration: ClinicalTrials.gov Identifier: NCT04437511.

APOE ε4's impact on response to amyloid therapies in early symptomatic Alzheimer's disease: Analyses from multiple clinical trials.

INTRODUCTION: Apolipoprotein E (APOE) ε4 may interact with response to amyloid-targeting therapies. METHODS: Aggregate data from trials enrolling participants with amyloid-positive, early symptomatic Alzheimer's disease (AD) were analyzed for disease progression. RESULTS: Pooled analysis of potentially efficacious antibodies lecanemab, aducanumab, solanezumab, and donanemab shows slightly better efficacy in APOE ε4 carriers than in non-carriers. Carrier and non-carrier mean (95% confidence interval) differences from placebo using Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) were -0.30 (-0.478, -0.106) and -0.20 (-0.435, 0.042) and AD Assessment Scale-Cognitive subscale (ADAS-Cog) values were -1.01 (-1.577, -0.456) and -0.80 (-1.627, 0.018), respectively. Decline in the APOE ε4 non-carrier placebo group was equal to or greater than that in carriers across multiple scales. Probability of study success increases as the representation of the carrier population increases. DISCUSSION: We hypothesize that APOE ε4 carriers have same or better response than non-carriers to amyloid-targeting therapies and similar or less disease progression with placebo in amyloid-positive trials. HIGHLIGHTS: Amyloid-targeting therapies had slightly greater efficacy in apolipoprotein E (APOE) ε4 carriers. Clinical decline is the same/slightly faster in amyloid-positive APOE ε4 non-carriers. Prevalence of non-carriers in trial populations could impact outcomes.

Donanemab in Early Alzheimer's Disease.

BACKGROUND: A hallmark of Alzheimer's disease is the accumulation of amyloid-ß (Aß) peptide. Donanemab, an antibody that targets a modified form of deposited Aß, is being investigated for the treatment of early Alzheimer's disease. METHODS: We conducted a phase 2 trial of donanemab in patients with early symptomatic Alzheimer's disease who had tau and amyloid deposition on positron-emission tomography (PET). Patients were randomly assigned in a 1:1 ratio to receive donanemab (700 mg for the first three doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks. The primary outcome was the change from baseline in the score on the Integrated Alzheimer's Disease Rating Scale (iADRS; range, 0 to 144, with lower scores indicating greater cognitive and functional impairment) at 76 weeks. Secondary outcomes included the change in scores on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog13), the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini-Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on PET. RESULTS: A total of 257 patients were enrolled; 131 were assigned to receive donanemab and 126 to receive placebo. The baseline iADRS score was 106 in both groups. The change from baseline in the iADRS score at 76 weeks was -6.86 with donanemab and -10.06 with placebo (difference, 3.20; 95% confidence interval, 0.12 to 6.27; P = 0.04). The results for most secondary outcomes showed no substantial difference. At 76 weeks, the reductions in the amyloid plaque level and the global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo. Amyloid-related cerebral edema or effusions (mostly asymptomatic) occurred with donanemab. CONCLUSIONS: In patients with early Alzheimer's disease, donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed. Longer and larger trials are necessary to study the efficacy and safety of donanemab in Alzheimer's disease. (Funded by Eli Lilly; TRAILBLAZER-ALZ ClinicalTrials.gov number, NCT03367403.).

Statistical properties of continuous composite scales and implications for drug development.

Little research has been conducted on the statistical properties of composite measures comprising linear combinations of continuous component scales. We assessed the quantitative relationship between the composites and their individual components regarding their abilities to detect treatment effects. In particular, we developed the mathematical derivation of the treatment effect size of a continuous composite in relation to the treatment effect sizes of its components and proved multiple properties of the composite. We demonstrated that the treatment effect size of a composite is greater than the minimum treatment effect size of its components and that above certain thresholds of correlations of components and ratios of component effect sizes, the composite may outperform its components. Examples from Alzheimer's disease (AD) clinical studies of solanezumab and donepezil using the composite Integrated AD Rating Scale (iADRS) and its components, the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and AD Cooperative Study-Activities of Daily Living inventory, instrumental items (ADCS-iADL) were consistent with the theoretical statistical properties. The understanding of the quantitative relationships between continuous composites and their components will be useful in clinical trial design and the development of new scales and composites across therapeutic areas.

Efficacy outcomes from 3 clinical trials of edivoxetine as adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment.

OBJECTIVE: Three studies examined whether edivoxetine (a highly selective norepinephrine reuptake inhibitor) had efficacy as adjunctive therapy for patients with major depressive disorder (DSM-IV-TR) who were partial responders to selective serotonin reuptake inhibitor (SSRI) treatment of at least 6 weeks' duration. METHOD: Studies were 8-week randomized, placebo-controlled trials with a 3-week double-blind placebo lead-in phase, conducted from December 16, 2010, to October 21, 2013. Patients entered the double-blind adjunctive treatment phase if they met randomization criteria (< 25% improvement on Montgomery-Asberg Depression Rating Scale [MADRS] and MADRS total score ≥ 14); patients not randomized remained on adjunctive placebo. Study 1 compared fixed-dose edivoxetine (12 or 18 mg daily) + SSRI (N = 231 and N = 230, respectively) with placebo + SSRI (N = 240); study 2 compared flexible-dose edivoxetine (12-18 mg daily) + SSRI (N = 232) and fixed-dose edivoxetine (6 mg daily) + SSRI (N = 226) with placebo + SSRI (N = 231); and study 3 compared flexible-dose edivoxetine (12-18 mg daily) + SSRI (N = 230) with placebo + SSRI (N = 219). The primary outcome was mean change from randomization baseline to week 8 in MADRS total score, analyzed using repeated measures analysis. RESULTS: Each trial failed to meet the primary and most of the secondary objectives. The least-squares mean changes in MADRS total score were as follows-study 1: -8.5 (edivoxetine 12 mg + SSRI), -8.7 (edivoxetine 18 mg + SSRI), and -7.8 (placebo + SSRI); study 2: -9.4 (edivoxetine 12-18 mg + SSRI), -9.6 (edivoxetine 6 mg + SSRI), and -9.4 (placebo + SSRI); and study 3: -8.7 (edivoxetine 12-18 mg + SSRI) and -8.5 (placebo + SSRI). CONCLUSIONS: Adjunctive edivoxetine treatment for patients with major depressive disorder who were partial responders to SSRIs did not significantly improve efficacy outcomes. TRIALS REGISTRATIONS: ClinicalTrials.gov identifiers: NCT01173601, NCT01187407, NCT01185340.

Safety and tolerability of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor antidepressants for patients with major depressive disorder.

OBJECTIVE: The aim of this analysis was to assess the safety profile of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor (SSRI) antidepressants. METHODS: A pooled analysis was conducted on data obtained from the integrated safety database of edivoxetine as adjunctive treatment to SSRIs. Safety and tolerability assessments included discontinuation rates, spontaneously reported treatment-emergent adverse events (TEAEs), clinical laboratory tests, blood pressure (BP) and pulse, and electrocardiograms (ECGs). RESULTS: The analysis included 1260 patients treated with adjunctive edivoxetine and 806 treated with adjunctive placebo. Study completion rates were 85.2% and 84.5% (p=0.994), respectively. Discontinuations due to adverse events were 4.9% and 3.5% (p=0.07), respectively. Significantly more patients in the adjunctive edivoxetine group compared with adjunctive placebo group reported at least one TEAE (56.8 vs 43.7%, p<0.001). The most common TEAEs (occurred ≥5% frequency) were hyperhidrosis, nausea, and tachycardia. Mean changes in sitting BP and pulse at the last visit were increased significantly in patients treated with adjunctive edivoxetine compared with adjunctive placebo (SBP: 2.7 vs 0.5 mm Hg, p<0.001; DBP: 4.1 vs 0.8 mm Hg, p<0.001; pulse: 8.8 vs -1.3 bpm, p<0.001). There were no clinically significant changes in laboratory measures. CONCLUSIONS: The tolerability and safety profile of edivoxetine as adjunctive treatment to SSRI antidepressants was consistent with its norepinephrine reuptake inhibitor mechanism of action, and was comparable with edivoxetine monotherapy treatment in patients with major depressive disorder.

Long-Term, Open-Label, Safety Study of Edivoxetine 12 to 18 mg Once Daily as Adjunctive Treatment for Patients With Major Depressive Disorder Who Are Partial Responders to Selective Serotonin Reuptake Inhibitor Treatment.

Long-term safety, tolerability, and efficacy of adjunctive edivoxetine hydrochloride (hereafter edivoxetine), a highly selective and potent norepinephrine reuptake inhibitor, was assessed in patients with major depressive disorder (MDD) experiencing partial response to selective serotonin reuptake inhibitor treatment. Data are from a multicenter, 54-week, open-label trial of adjunctive edivoxetine 12 to 18 mg once daily in patients with MDD who had experienced partial response by history to 6 or more weeks of current selective serotonin reuptake inhibitor therapy and who had a 17-item GRID Hamilton Rating Scale for Depression total score 16 or higher at study entry. Safety measures included discontinuation rate, treatment-emergent adverse events, serious adverse events, and vital signs. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale. Of 608 patients, 328 (54%) completed the open-label adjunctive treatment. Study discontinuation due to adverse events occurred in 17.0%, and there were 13 serious adverse events (1 death). Treatment-emergent adverse events 5% or higher were nausea, hyperhidrosis, constipation, headache, dry mouth, dizziness, vomiting, insomnia, and upper respiratory tract infection. Mean increases were observed in systolic blood pressure (range, 0.0-2.3 mm Hg), diastolic blood pressure (range, 1.9-3.3 mm Hg), and pulse (range, 5.9-8.4 beats per minute). Mean improvements on the Montgomery-Åsberg Depression Rating Scale (-17.0) were observed from baseline to week 54. The safety profile from this study provides an overview of outcomes associated with edivoxetine and norepinephrine reuptake inhibition as an adjunctive treatment in patients with MDD who were treated up to 1 year.

Further evidence for the reliability and validity of the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ).

BACKGROUND: The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) was developed to assess clinically relevant cognitive and physical symptoms associated with depression that are not adequately assessed by traditional measures. Although the CPFQ has been shown previously to be a reliable and valid measure, the purpose of the present study was to provide additional evidence using larger samples from 4 independent clinical trials that were designed to test the efficacy and safety of different antidepressants. METHODS: The psychometric analyses were based on data from 4 independent clinical trials that were designed to test the safety and efficacy of different antidepressants. Reliability of the items and of the overall questionnaire was evaluated with principal components analysis, whereas validity was assessed by associations of the questionnaire scores with convergent and divergent external criteria. RESULTS: Overall, the results have replicated previous findings that the CPFQ has good internal reliability. Validation also is strengthened by the demonstration of predictive differences among known groups as well as a sensitivity to change with antidepressant treatment. CONCLUSIONS: Results support the use of the CPFQ as a valuable instrument for the detection of clinically relevant symptoms that are not captured by typical measures of depression used for the assessment of treatment outcomes.

Clinical relevance of fatigue as a residual symptom in major depressive disorder.

Residual symptoms of major depressive disorder (MDD) following treatment are increasingly recognized as having a negative impact on the patient because of their association with lack of remission, poorer psychosocial functioning, and a more chronic course of depression. Although the effects of specific residual symptoms have not been as systematically studied, several symptoms, including fatigue, sleep disturbance, anxiety, and concentration difficulties, commonly occur as part of the residual state in MDD. In particular, the relatively high prevalence of residual fatigue suggests that this symptom is not being adequately addressed by standard antidepressant therapies. A review of the clinical relevance of residual fatigue was undertaken, using the published literature with respect to its assessment, neurobiology, and treatment implications. The findings of this review suggest that fatigue is highly prevalent as a residual symptom; its response to treatment is relatively poor or delayed; and the presence of residual fatigue is highly predictive of inability to achieve remission with treatment as well as impaired psychosocial functioning. Recognition of the significant consequences of residual fatigue should reinforce the need for further therapeutic interventions to help reduce the impact of this symptom of MDD.

Visual vigilance in drivers with obstructive sleep apnea.

OBJECTIVE: To determine the effects of obstructive sleep apnea (OSA) on visual vigilance during simulated automobile driving. METHODS: Twenty-five drivers with OSA and 41 comparison drivers participated in an hour-long drive in a high-fidelity driving simulator. Drivers responded to light targets flashed at seven locations across the forward horizon. Dependent measures were percent correct [hit rate (HR)] and reaction time (RT). Self-assessment of sleepiness used the Stanford Sleepiness Scale (SSS) before and after the drive and the Epworth Sleepiness Scale (ESS). RESULTS: OSA drivers showed reduced vigilance based on lower HR than comparison drivers, especially for peripheral targets (80.7+/-14.8% vs. 86.7+/-8.8%, P=.03). OSA drivers were sleepier at the end of the drive than comparison drivers (SSS=4.2+/-1.2 vs. 3.6+/-1.2, P=.03), and increased sleepiness correlated with decreased HR only in those with OSA (r=-0.49, P=.01). Lower HR and higher post-drive SSS predicted greater numbers of driving errors in all subjects. Yet, ESS, predrive SSS, and most objective measures of disease severity failed to predict driving and vigilance performance in OSA. CONCLUSIONS: Reduced vigilance for peripheral visual targets indicates that OSA drivers have restriction of their effective field of view, which may partly explain their increased crash risk. This fatigue-related decline in attention is predicted by increased subjective sleepiness during driving. These findings may suggest a means of identifying and counseling high-risk drivers and aid in the development of in-vehicle alerting and warning devices.

Change blindness, aging, and cognition.

Change blindness (CB), the inability to detect changes in visual scenes, may increase with age and early Alzheimer's disease (AD). To test this hypothesis, participants were asked to localize changes in natural scenes. Dependent measures were response time (RT), hit rate, false positives (FP), and true sensitivity (d'). Increased age correlated with increased sensitivity and RT; AD predicted even slower RT. Accuracy and RT were negatively correlated. Differences in FP were nonsignificant. CB correlated with impaired attention, working memory, and executive function. Advanced age and AD were associated with increased CB, perhaps due to declining memory and attention. CB could affect real-world tasks, like automobile driving.

USEFUL FIELD OF VIEW IMPAIRMENTS IN DRIVERS WITH OBSTRUCTIVE SLEEP APNEA.

As a group, drivers with obstructive sleep apnea (OSA) have an increased risk for motor vehicle crashes, but determining individual crash risk is difficult. We tested the hypothesis that drivers with OSA have impaired visual attention, as indexed by reduced useful field of view (UFOV), a predictor of high-risk driving. Forty-one drivers with untreated OSA and 50 comparison drivers were assessed by UFOV. OSA drivers performed significantly worse than controls on all UFOV subtests and had reduced UFOV as indicated by a higher mean total UFOV score (p = 0.0017). However, only 4 OSA and 2 control drivers had values indicative of high crash risk (UFOV reduction >23%). Drivers with OSA have reduced UFOV compared to drivers without neurological or sleep disorders. However, as UFOV identifies few high-risk drivers, its role in assessing crash risk in an unselected population of drivers with OSA appears to be limited.

First and second-order motion perception after focal human brain lesions.

Perception of visual motion includes a first-order mechanism sensitive to luminance changes and a second-order motion mechanism sensitive to contrast changes. We studied neural substrates for these motion types in 142 subjects with visual cortex lesions, 68 normal controls and 28 brain lesion controls. On first-order motion, the visual cortex lesion group performed significantly worse than normal controls overall and in each hemifield, but second-order motion did not differ. Only one individual showed a selective second-order motion deficit. Motion deficits were seen with lesions outside the small occipito-temporal region thought to contain a human homolog of motion processing area MT (V5), suggesting that many areas of human brain process visual motion.

Impaired visual search in drivers with Parkinson's disease.

OBJECTIVE: To assess the ability for visual search and recognition of roadside targets and safety errors during a landmark and traffic sign identification task in drivers with Parkinson's disease (PD). METHODS: Seventy-nine drivers with PD and 151 neurologically normal older adults underwent a battery of visual, cognitive, and motor tests. The drivers were asked to report sightings of specific landmarks and traffic signs along a four-lane commercial strip during an experimental drive in an instrumented vehicle. RESULTS: The drivers with PD identified significantly fewer landmarks and traffic signs, and they committed more at-fault safety errors during the task than control subjects, even after adjusting for baseline errors. Within the PD group, the most important predictors of landmark and traffic sign identification rate were performances on Useful Field of View (visual speed of processing and attention) and Complex Figure Test-Copy (visuospatial abilities). Trail Making Test (B-A), a measure of cognitive flexibility independent of motor function, was the only independent predictor of at-fault safety errors in drivers with PD. INTERPRETATION: The cognitive and visual deficits associated with PD resulted in impaired visual search while driving, and the increased cognitive load during this task worsened their driving safety.