Puja Aggarwal

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.

<h3>Background and Objectives</h3> Accumulation of tau pathology in Alzheimer’s disease (AD) correlates with cognitive decline. Anti-tau immunotherapies were proposed as potential interventions in AD. While antibodies targeting N-terminal tau failed to demonstrate clinical efficacy in prodromal-to-mild AD, their utility at other disease stages was not yet evaluated. Lauriet is a phase II study of an anti-tau monoclonal antibody, semorinemab, in patients with mild-to-moderate AD. <h3>Methods</h3> The phase II Lauriet study included a randomized, placebo-controlled, double-blind period, during which participants with mild-to-moderate AD received intravenous semorinemab 4500 mg or placebo every 4 weeks for 48 or 60 weeks. Participants who chose to continue in the subsequent optional open-label extension (OLE) received semorinemab 4500 mg every 4 weeks for up to 96 weeks. Co-primary efficacy endpoints were change from baseline to week 49 or 61 on the 11-item version of the Alzheimer’s disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. Secondary efficacy endpoints included change from baseline on the Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Safety, pharmacokinetics and pharmacodynamic effects were also evaluated. <h3>Results</h3> Between Dec 3, 2018 and Feb 27, 2020, 624 individuals were screened, 272 participants were randomized, and 238 were included in the modified intent-to-treat population [received ≥1 dose(s) of study medication and underwent baseline and ≥1 post-baseline assessment(s)]. Baseline characteristics were well-balanced. At week 49, the semorinemab arm demonstrated a 42.2% reduction (-2.89 points, 95% confidence interval: -4.56 to -1.21, p=0.0008) in decline on ADAS-Cog11 (co-primary endpoint) relative to placebo. However, no treatment effects were observed on the ADCS-ADL (co-primary endpoint; absolute difference between the two treatment arms in ADCS-ADL score change from baseline of -0.83 points, 95% confidence interval: -3.39, 1.72, p=0.52), or on the MMSE or CDR-SB (secondary endpoints). Semorinemab was safe and well-tolerated. <h3>Discussion</h3> Based on the results of the pre-specified co-primary endpoints this study was negative. While semorinemab had a significant effect on cognition measured by ADAS-Cog11, this effect did not extend to improved functional or global outcomes. These results may warrant further exploration of semorinemab or other anti-tau therapies in mild to moderate AD. <h3>Classification of Evidence</h3> This study provides Class I evidence that semorinemab does not slow functional decline in patients with mild-to-moderate AD. <h3>Trial Registration Information</h3> The Lauriet study is registered on ClinicalTrials.gov, NCT03828747 (status: active, not recruiting), and EudraCT 2018-003398-87.

Purpose: Merger is a corporate restructuring strategy that affects the performance of the company on many parameters. This study aims to examine the growth of M&amp;A transactions in India in last two decades and the impact of merger on the accounting-based performance of the acquiring company. Methodology: The data of 68 mergers during the year 2007-08 - 2011-12 is analysed to capture the said impact. The accounting-based performance is measured on seven variables divided into three categories- profitability, liquidity and solvency. The accounting-based performance five years’ pre-merger is compared with five years’ post-merger. The similar comparison is done for 3 years pre and post-merger. Average of all the 7 parameters pre and post-merger are compared arithmetically and then using paired sample ‘t’test. The firms were also divided into manufacturing and service sector firms to see the impact of merger on different categories of firms. Findings: We found that merger has significantly impacted profitability and liquidity of the acquiring firm positively in five years but had no significant impact on solvency position of the company. Service sector firms have outperformed manufacturing firms and started showing significant improvement in accounting variables in medium term. Originality: We assure the originality of the work done in this article.

Importance: Lower cranial neuropathy (LCNP) is a rare but potentially disabling result of radiotherapy and other head and neck cancer therapies. Survivors who develop late LCNP may experience profound functional impairment, with deficits in swallowing, speech, and voice. Objective: To investigate the association of late LCNP with severity of cancer treatment-related symptoms and subsequent general functional impairment among oropharyngeal cancer (OPC) survivors. Design, Setting, and Participants: This cross-sectional survey study analyzed 889 OPC survivors nested within a retrospective cohort of OPC survivors treated at MD Anderson Cancer Center from January 1, 2000, to December 31, 2013. Eligible survey participants were disease free and completed OPC treatment 1 year or more before the survey. Data analysis was performed from October 10, 2017, to March 15, 2018. Exposures: Late LCNP defined by onset 3 months or more after cancer therapy. Main Outcomes and Measures: The primary outcome variable was the mean of the top 5 most severely scored symptoms of all 22 core and head and neck cancer-specific symptoms from the MD Anderson Symptom Inventory Head and Neck Cancer Module (MDASI-HN). Secondary outcomes included mean MDASI-HN interference scores and single-item scores of the most severe symptoms. Multivariate models regressed MDASI-HN scores on late LCNP status, adjusting for clinical covariates. Results: Overall, 36 of 889 OPC survivors (4.0%) (753 [84.7%] male; 821 [92.4%] white; median [range] age, 56 [32-84] years; median [range] survival time, 7 [1-16] years) developed late LCNP. Late LCNP was significantly associated with worse mean top 5 MDASI-HN symptom scores (coefficient, 1.54; 95% CI, 0.82-2.26), adjusting for age, survival time, sex, therapeutic modality, T stage, subsite, type of radiotherapy, smoking, and normal diet before treatment. Late LCNP was also significantly associated with single-item scores for difficulty swallowing or chewing (coefficient, 2.25; 95% CI, 1.33-3.18), mucus (coefficient, 1.97; 95% CI, 1.03-2.91), fatigue (coefficient, 1.35; 95% CI, 0.40-2.21), choking (coefficient, 1.53; 95% CI, 0.65-2.41), and voice or speech symptoms (coefficient, 2.30; 95% CI, 1.60-3.03) in multivariable models. Late LCNP was not significantly associated with mean interference scores after correction for multiple comparisons (mean interference coefficient, 0.72; 95% CI, 0.09-1.35). Conclusions and Relevance: In this large survey study, OPC survivors with late LCNP reported worse cancer treatment-related symptoms, a finding suggesting an association between late LCNP and symptom burden. This research may inform the development and implementation of strategies for LCNP surveillance and management.

BACKGROUND: The purpose of this study was to quantify the association of late lower cranial neuropathy (late LCNP) with swallowing-related quality of life (QOL) and functional status among long-term oropharyngeal cancer (OPC) survivors. METHODS: Eight hundred eighty-nine OPC survivors (median survival time: 7 years) who received primary treatment at a single institution between January 2000 and December 2013 completed a cross-sectional survey (56% response rate) that included the MD Anderson Dysphagia Inventory (MDADI) and self-report of functional status. Late LCNP events ≥3 months after cancer therapy were abstracted from medical records. Multivariate models regressed MDADI scores on late LCNP status adjusting for clinical covariates. RESULTS: Overall, 4.0% (n = 36) of respondents developed late LCNP with median time to onset of 5.25 years post-treatment. LCNP cases reported significantly worse mean composite MDADI (LCNP: 68.0 vs no LCNP: 80.2; P < .001). Late LCNP independently associated with worse mean composite MDADI (β = -6.7, P = .02; 95% confidence interval [CI], -12.0 to -1.3) as well as all MDADI domains after multivariate adjustment. LCNP cases were more likely to have a feeding tube at time of survey (odds ratio [OR] = 20.5; 95% CI, 8.6-48.9), history of aspiration pneumonia (OR = 23.5; 95% CI, 9.6-57.6), and tracheostomy (OR = 26.9; 95% CI, 6.0-121.7). CONCLUSIONS: In this large survey study, OPC survivors with late LCNP reported significantly poorer swallowing-related QOL and had significantly higher likelihood of poor functional status. Further efforts are necessary to optimize swallowing outcomes to improve QOL in this subgroup of survivors.