Rasagiline Effects on Glucose Metabolism, Cognition, and Tau in Alzheimer’s Dementia

Background: A Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer\u27s disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose–positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points. Methods: This was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model. Results: Fifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal (P \u3c 0.025), anterior cingulate (P \u3c 0.041), and striatal (P \u3c 0.023) regions. Clinical measures showed benefit in quality of life (P \u3c 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non-significant directional favoring of rasagiline; no effects were observed in Alzheimer\u27s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group. Discussion: These outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof-of-concept design with biomarkers to characterize patient and detect treatment response

Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer's Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer's disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid β peptides (Aβ1-40, Aβ1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology

Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation

Hepatic veno-occlusive disease (VOD) is a serious complication of stem cell transplantation in children. VOD is characterized by rapid weight gain, hepatomegaly, hyperbilirubinemia and ascites. The pathogenesis of VOD is thought to involve chemotherapy and radiation-induced damage to the sinusoidal endothelium, resulting in endothelial injury, microthrombosis, subendothelial damage and cytokine activation. These processes lead to concomitant progressive hepatocellular dysfunction and subsequent fluid retention and renal impairment. Severe VOD is typically associated with multiorgan failure and high mortality. A number of possible strategies for the prevention and/or treatment of VOD in children have been investigated. The most promising agent to date is defibrotide, a novel polydeoxyribonucleotide with fibrinolytic properties but no major bleeding risk. Numerous studies, including Phase II/III trials, have shown clinical benefit in pediatric patients with the use of defibrotide treatment and prophylaxis. This review discusses VOD in children and focuses on therapeutic options, including defibrotide, in this patient population

Variable Patterns of Continuous Morphine Infusions at End of Life

BackgroundContinuous morphine infusions (CMIs) treat pain and dyspnea at the end of life (EOL). CMIs may be initiated at an empiric rate and/or are rapidly escalated without proper titration.ObjectiveThe study objective was to evaluate CMI patterns at the EOL.MethodsThis single-center, retrospective chart review evaluated adult patients who died while receiving CMI at EOL. Patient demographics and opioid dosing information were extracted from an electronic medical record. Twenty-four hour IV morphine equivalent was calculated prior to CMI initiation and at the time of death.ResultsOf the 190 patient charts, 63.2% (n=120) received no bolus doses prior to CMI initiation. Mean 24-hour IV morphine equivalent prior to CMI initiation was 49.3 mg (range: 0-1200 mg, SD 384.9) and at time of death was 267.1 mg (12.0-5193.2 mg, SD 442.2), representing an increase of +442%. Mean CMI starting rate was 3.3 mg/hour (0.4-30.0 mg/hour, SD 3.6) with titration at time of death to a mean of 7.7 mg/hour (0.4-70.0 mg/hour, SD 9.4), representing an increase of +130%. Mean number of CMI rate adjustments was 2.5 (0-5, SD 3.3); and number of bolus doses administered between titrations was 4.2 (0-27, SD 4.8). Mean time from CMI initiation to death was 15.5 hours (0.05-126.9 hours, SD 21.7). There was a negative association between rate of infusion increase per hour and total number of hours on CMI (r=-0.2, p=0.0062).ConclusionsHospitalized patients at EOL had a much higher 24-hour IV morphine equivalents and CMI rates at time of death compared to CMI initiation. Variability was observed in the number of CMI rate adjustments and the number of bolus doses administered

Variable Patterns of Continuous Morphine Infusions at End of Life

Background: Continuous morphine infusions (CMIs) treat pain and dyspnea at the end of life (EOL). CMIs may be initiated at an empiric rate and/or are rapidly escalated without proper titration. Objective: The study objective was to evaluate CMI patterns at the EOL. Methods: This single-center, retrospective chart review evaluated adult patients who died while receiving CMI at EOL. Patient demographics and opioid dosing information were extracted from an electronic medical record. Twenty-four hour IV morphine equivalent was calculated prior to CMI initiation and at the time of death. Results: Of the 190 patient charts, 63.2% (n=120) received no bolus doses prior to CMI initiation. Mean 24-hour IV morphine equivalent prior to CMI initiation was 49.3 mg (range: 0–1200 mg, SD 384.9) and at time of death was 267.1 mg (12.0–5193.2 mg, SD 442.2), representing an increase of +442%. Mean CMI starting rate was 3.3 mg/hour (0.4–30.0 mg/hour, SD 3.6) with titration at time of death to a mean of 7.7 mg/hour (0.4–70.0 mg/hour, SD 9.4), representing an increase of +130%. Mean number of CMI rate adjustments was 2.5 (0–5, SD 3.3); and number of bolus doses administered between titrations was 4.2 (0–27, SD 4.8). Mean time from CMI initiation to death was 15.5 hours (0.05–126.9 hours, SD 21.7). There was a negative association between rate of infusion increase per hour and total number of hours on CMI (r=−0.2, p=0.0062). Conclusions: Hospitalized patients at EOL had a much higher 24-hour IV morphine equivalents and CMI rates at time of death compared to CMI initiation. Variability was observed in the number of CMI rate adjustments and the number of bolus doses administered

Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimers disease (BenfoTeam).

BACKGROUND: Benfotiamine provides an important novel therapeutic direction in Alzheimers disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. OBJECTIVE: To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. METHODS: This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. CONCLUSION: The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360