Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial

Tau plays a key role in Alzheimer’s disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989

Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study

Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. Conclusions Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. Trial registration Registered in July 2016 at clinicaltrials.gov (NCT02847442)

White Paper: Umgang mit Zielen der BLV als Grundlage für die Strukturevaluation

In der Bund-Länder-Vereinbarung (BLV) zu Aufbau und Förderung einer Nationalen Forschungsdateninfrastruktur (NFDI) (im Folgenden BLV-NFDI) wird in §1 festgehalten, dass mit der Förderung "eine Etablierung und Fortentwicklung eines übergreifenden Forschungsdatenmanagements" und damit eine "Steigerung der Effizienz des gesamten Wissenschaftssystems verfolgt" wird. In der BLV-NFDI werden dazu sieben Ziele vorgegeben, die eine Verfeinerung dieser Hauptziele darstellen. Dieses White Paper formuliert das gemeinsame Verständnis der beteiligten Konsortien für die sieben in der BLV-NFDI vorgegebenen Ziele. Auf der Grundlage dieses Verständnisses hat die Task Force Evaluation und Reporting Vorschläge gemacht, wie das Erreichen der Ziele erfasst, beschrieben und gemessen werden kann

Collaborative work in NFDI

The non-profit association National Research Data Infrastructure (NFDI) promotes science and research through a National Research Data Infrastructure. Its aim is to develop and establish an overarching research data management (RDM) for Germany and to increase the efficiency of the entire German science system. After a two-and-a-half year build up phase, the process of adding new consortia, each representing a different data domain, has ended in March 2023. NFDI now has 26 disciplinary consortia (and one additional basic service collaboration). Now the full extent of cross-consortial interaction is beginning to show

White Paper: Umgang mit Zielen der BLV als Grundlage für die Strukturevaluation

&lt;p&gt;In der &lt;a href="https://www.gwk-bonn.de/fileadmin/Redaktion/Dokumente/Papers/NFDI.pdf"&gt;Bund-L&auml;nder-Vereinbarung (BLV) zu Aufbau und F&ouml;rderung einer Nationalen Forschungsdateninfrastruktur (NFDI)&lt;/a&gt; (im Folgenden BLV-NFDI) wird in &sect;1 festgehalten, dass mit der F&ouml;rderung &quot;eine Etablierung und Fortentwicklung eines &uuml;bergreifenden Forschungsdatenmanagements&quot; und damit eine &quot;Steigerung der Effizienz des gesamten Wissenschaftssystems verfolgt&quot; wird. In der BLV-NFDI werden dazu sieben Ziele vorgegeben, die eine Verfeinerung dieser Hauptziele darstellen. Dieses White Paper formuliert das gemeinsame Verst&auml;ndnis der beteiligten Konsortien f&uuml;r die sieben in der BLV-NFDI vorgegebenen Ziele. Auf der Grundlage dieses Verst&auml;ndnisses hat die Task Force Evaluation und Reporting Vorschl&auml;ge gemacht, wie das Erreichen der Ziele erfasst, beschrieben und gemessen werden kann.&lt;/p&gt

Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial

Tau plays a key role in Alzheimer’s disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989

Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome:a randomised, double-blind, placebo-controlled trial

The air-sea gas transfer velocity k is frequently estimated as an empirical function of wind speed. However, it is widely recognized that k depends on processes other than wind speed alone. The small-eddy model, which describes periodic events of small eddies disturbing the sea surface with water from below, suggests a direct relation between k and the dissipation rate of turbulent kinetic energy E at the air-sea interface. This relation has been proven both in laboratories and in the field in various freshwater and coastal environments, but to date has not been verified in open ocean conditions. Here, concurrent North Atlantic field observations of E and eddy covariance measurements of DMS and CO2 air-sea gas flux are presented. Using E measurements, we compare the small-eddy model at various depths to previously published observations. Extrapolating the measured E profiles to the thickness of the viscous sublayer allows us to formulate a function of k that depends solely on the water side friction velocity uw, which can be inferred from direct eddy covariance measurements of the air-side friction velocity ua. These field observations are generally consistent with the theoretical small-eddy model. Utilizing a variable Schmidt number exponent in the model, rather than a constant value of 1/2 yields improved agreement between model and observations