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  1. Article ; Online: A randomized, double-blind, placebo-controlled phase 2 study to assess safety, tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis.

    Weemering, Daphne N / Midei, Mark / Milner, Peter / Gopalakrishnan, Vidhya / Kumar, Anil / Dannenberg, Andrew J / Bunte, Tommy M / Foucher, Juliette / Ingre, Caroline / Ķēniņa, Viktorija / Rallmann, Karin / van den Berg, Leonard H / van Eijk, Ruben P A

    European journal of neurology

    2023  Volume 30, Issue 12, Page(s) 3722–3731

    Abstract: Background and purpose: RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS).! ...

    Abstract Background and purpose: RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS).
    Methods: We conducted a randomized, multicenter, placebo-controlled clinical trial. Patients with ALS were randomly allocated to receive either RT001 or placebo for 24 weeks. After the double-blind period, all patients received RT001 during an open-label phase for 24 weeks. The primary outcome measures were safety and tolerability. Key efficacy outcomes included the ALS Functional Rating Scale (ALSFRS-R), percent predicted slow vital capacity, and plasma neurofilament light chain concentration.
    Results: In total, 43 patients (RT001 = 21; placebo = 22) were randomized. RT001 was well tolerated; one patient required dose reduction due to adverse events (AEs). Numerically, there were more AEs in the RT001 group compared to the placebo group (71% versus 55%, p = 0.35), with gastrointestinal symptoms being the most common (43% in RT001, 27% in placebo, p = 0.35). Two patients in the RT001 group experienced a serious AE, though unrelated to treatment. The least-squares mean difference in ALSFRS-R total score at week 24 of treatment was 1.90 (95% confidence interval = -1.39 to 5.19) in favor of RT001 (p = 0.25). The directions of other efficacy outcomes favored RT001 compared to placebo, although no inferential statistics were performed.
    Conclusions: Initial data indicate that RT001 is safe and well tolerated. Given the exploratory nature of the study, a larger clinical trial is required to evaluate its efficacy.
    MeSH term(s) Humans ; Amyotrophic Lateral Sclerosis/diagnosis ; Linoleic Acids/therapeutic use ; Double-Blind Method ; Treatment Outcome
    Chemical Substances RT001 ; Linoleic Acids
    Language English
    Publishing date 2023-08-21
    Publishing country England
    Document type Randomized Controlled Trial ; Multicenter Study ; Clinical Trial, Phase II ; Journal Article
    ZDB-ID 1280785-0
    ISSN 1468-1331 ; 1351-5101 ; 1471-0552
    ISSN (online) 1468-1331
    ISSN 1351-5101 ; 1471-0552
    DOI 10.1111/ene.16020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 592: Show issues

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  2. Article ; Online: The ALSFRS-R Summit: a global call to action on the use of the ALSFRS-R in ALS clinical trials.

    Genge, Angela / Cedarbaum, Jesse M / Shefner, Jeremy / Chio, Adriano / Al-Chalabi, Ammar / Van Damme, Philip / McDermott, Chris / Glass, Jonathan / Berry, James / van Eijk, Ruben P A / Fournier, Christina / Grosskreutz, Julian / Andrews, Jinsy / Bertone, Vanessa / Bunte, Tommy M / Couillard, Mathias / Cummings, Cathy / Kittle, Gale / Polzer, John /
    Salmon, Kristiana / Straub, Corey / van den Berg, Leonard H

    Amyotrophic lateral sclerosis & frontotemporal degeneration

    2024  Volume 25, Issue 3-4, Page(s) 382–387

    Abstract: The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was developed more than 25 years ago as an instrument to monitor functional change over time in patients with ALS. It has since been revised and extended to meet the needs of high data ... ...

    Abstract The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was developed more than 25 years ago as an instrument to monitor functional change over time in patients with ALS. It has since been revised and extended to meet the needs of high data quality in ALS trials (ALSFRS-R), however a full re-validation of the scale was not completed. Despite this, the scale has remained a primary outcome measure in clinical trials. We convened a group of clinical trialists to discuss and explore opportunities to improve the scale and propose alternative measures. In this meeting report, we present a call to action on the use of the ALSFRS-Revised scale in clinical trials, focusing on the need for (1) harmonization of the ALSFRS-R administration globally, (2) alignment on a set of recommendations for clinical trial design and statistical analysis plans (SAPs), and (3) use of additional outcome measures.
    MeSH term(s) Humans ; Amyotrophic Lateral Sclerosis/diagnosis ; Amyotrophic Lateral Sclerosis/drug therapy ; Severity of Illness Index ; Disease Progression
    Language English
    Publishing date 2024-02-23
    Publishing country England
    Document type Journal Article
    ZDB-ID 2705049-X
    ISSN 2167-9223 ; 2167-8421
    ISSN (online) 2167-9223
    ISSN 2167-8421
    DOI 10.1080/21678421.2024.2320880
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  3. Article ; Online: Development of a Rasch-Built Amyotrophic Lateral Sclerosis Impairment Multidomain Scale to Measure Disease Progression in ALS.

    de Jongh, Adriaan D / van Eijk, Ruben P A / Bakker, Leonhard A / Bunte, Tommy M / Beelen, Anita / van der Meijden, Conny / van Es, Michael A / Visser-Meily, Johanna M A / Kruitwagen, Esther T / Veldink, Jan H / van den Berg, Leonard H

    Neurology

    2023  Volume 101, Issue 6, Page(s) e602–e612

    Abstract: Background and objectives: Current scales used in amyotrophic lateral sclerosis (ALS) attempt to summarize different functional domains or "dimensions" into 1 overall score, which may not accurately characterize the individual patient's disease severity ...

    Abstract Background and objectives: Current scales used in amyotrophic lateral sclerosis (ALS) attempt to summarize different functional domains or "dimensions" into 1 overall score, which may not accurately characterize the individual patient's disease severity or prognosis. The use of composite score risks declaring treatments ineffective if not all dimensions of ALS disease progression are affected equally. We aimed to develop the ALS Impairment Multidomain Scale (AIMS) to comprehensively characterize disease progression and increase the likelihood of identifying effective treatments.
    Methods: The Revised ALS Functional Rating Scale (ALSFRS-R) and a preliminary questionnaire, based on literature review and patient input, were completed online by patients from the Netherlands ALS registry at bimonthly intervals over a period of 12 months. A 2-week test-retest, factor analysis, Rasch analysis, and a signal-to-noise optimization strategy were performed to create a multidomain scale. Reliability, longitudinal decline, and associations with survival were evaluated. The sample size required to detect a 35% reduction in progression rate over 6 or 12 months was assessed for a clinical trial that defines the ALSFRS-R or AIMS subscales as a primary endpoint family.
    Results: The preliminary questionnaire, consisting of 110 questions, was completed by 367 patients. Three unidimensional subscales were identified, and a multidomain scale was constructed with 7 bulbar, 11 motor, and 5 respiratory questions. Subscales fulfilled Rasch model requirements, with excellent test-retest reliability of 0.91-0.94 and a strong relationship with survival (
    Discussion: We developed the AIMS, consisting of unidimensional bulbar, motor, and respiratory subscales, which may characterize disease severity better than a total score. AIMS subscales have high test-retest reliability, are optimized to measure disease progression, and are strongly related to survival time. The AIMS can be easily administered and may increase the likelihood of identifying effective treatments in ALS clinical trials.
    MeSH term(s) Humans ; Amyotrophic Lateral Sclerosis ; Reproducibility of Results ; Prognosis ; Probability ; Disease Progression
    Language English
    Publishing date 2023-06-13
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 207147-2
    ISSN 1526-632X ; 0028-3878
    ISSN (online) 1526-632X
    ISSN 0028-3878
    DOI 10.1212/WNL.0000000000207483
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  4. Article ; Online: A placebo-controlled trial to investigate the safety and efficacy of Penicillin G/Hydrocortisone in patients with ALS (PHALS trial).

    Van Es, Michael A / Van Eijk, Ruben P A / Bunte, Tommy M / Van Den Berg, Leonard H

    Amyotrophic lateral sclerosis & frontotemporal degeneration

    2020  Volume 21, Issue 7-8, Page(s) 584–592

    Abstract: Objective: A recent case-series described patients with ALS to improve and/or stabilize after treatment with intravenous high-dose Penicillin G/Hydrocortisone (PenGH). In this study, we determine the safety and efficacy of intravenous PenGH versus ... ...

    Abstract Objective: A recent case-series described patients with ALS to improve and/or stabilize after treatment with intravenous high-dose Penicillin G/Hydrocortisone (PenGH). In this study, we determine the safety and efficacy of intravenous PenGH versus placebo in combination with riluzole in patients with ALS.
    Methods: Patients diagnosed with ALS according to the El Escorial criteria were randomized double-blind to four quarterly cycles of 21 d of intravenous PenGH or placebo in a 5:3 ratio. The primary outcome was change from baseline to week 48 in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). Secondary outcomes were lung function, muscle strength, plasma creatinine, clinical stage, gastrostomy placement, quality of life and occurrence of adverse of events.
    Results: In total, 16 patients were randomized (10 PenGH and 6 placebo), of which 6 (40%) completed the study. Patients treated with PenGH progressed with 2.2 (95% CI 1.1-3.3) ALSFRS-R points per month and PenGH treatment did not halt disease progression (
    Conclusions: Treatment with PenGH does not halt disease or reverse progression in patients with ALS and showed no statistical difference with those who received placebo. Prolonged intravenous administration therapies may inflate thrombosis risk.
    MeSH term(s) Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Humans ; Hydrocortisone ; Penicillin G ; Quality of Life
    Chemical Substances Penicillin G (Q42T66VG0C) ; Hydrocortisone (WI4X0X7BPJ)
    Language English
    Publishing date 2020-07-06
    Publishing country England
    Document type Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 2705049-X
    ISSN 2167-9223 ; 2167-8421
    ISSN (online) 2167-9223
    ISSN 2167-8421
    DOI 10.1080/21678421.2020.1788093
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    Zs.A 5874: Show issues Location:
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  5. Article ; Online: Using the ALSFRS-R in multicentre clinical trials for amyotrophic lateral sclerosis: potential limitations in current standard operating procedures.

    Bakers, Jaap N E / de Jongh, Adriaan D / Bunte, Tommy M / Kendall, Lindsay / Han, Steve S / Epstein, Noam / Lavrov, Arseniy / Beelen, Anita / Visser-Meily, Johanna M A / van den Berg, Leonard H / van Eijk, Ruben P A

    Amyotrophic lateral sclerosis & frontotemporal degeneration

    2021  Volume 23, Issue 7-8, Page(s) 500–507

    Abstract: ... Objective: ... Uniform data collection is fundamental for multicentre clinical trials. We aim to determine the variability, between ALS trial centers, in the prevalence of unexpected or implausible improvements in the revised ALS functional rating ... ...

    Abstract Objective: Uniform data collection is fundamental for multicentre clinical trials. We aim to determine the variability, between ALS trial centers, in the prevalence of unexpected or implausible improvements in the revised ALS functional rating scale (ALSFRS-R) score, and its associations with individual patient and item characteristics.Methods: We used data from two multicentre studies to estimate the prevalence of an unexpected increase or implausible improvement in the ALSFRS-R score, defined as an increase of 5 points or more between two consecutive, monthly visits. For each patient with a 5-point or more increase, we evaluated the individual contribution of each ALSFRS-R item.Results: Longitudinal ALSFRS-R scores, originating from 114 trial centers enrolling a total of 1,240 patients, were analyzed. A 5-point or more increase in ALSFRS-R total score was found in 151 (12.2%) patients, with prevalence per study center ranging from 0% to 83%. Bulbar onset, faster disease progression at enrollment, and a lower ALSFRS-R score at baseline were associated with a sudden 5-point or more increase in the ALSFRS-R total score. ALSFRS-R items 2 (saliva), 9 (stairs), 10 (dyspnea), and 11 (orthopnea) were the primary drivers when a 5-point or more increase occurred.Conclusions: Sudden 5-point or more increases in ALSFRS-R total scores between two consecutive visits are relatively common. These sudden increases were not found to occur with equal frequency in trial centers; which underscores the need for amending existing standard operating procedures toward a universal version and monitoring of data quality during the study, in multicentre research.
    MeSH term(s) Humans ; Amyotrophic Lateral Sclerosis/diagnosis ; Amyotrophic Lateral Sclerosis/epidemiology ; Amyotrophic Lateral Sclerosis/therapy ; Severity of Illness Index ; Disease Progression
    Language English
    Publishing date 2021-12-24
    Publishing country England
    Document type Multicenter Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2705049-X
    ISSN 2167-9223 ; 2167-8421
    ISSN (online) 2167-9223
    ISSN 2167-8421
    DOI 10.1080/21678421.2021.2016838
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  6. Article ; Online: Accelerometry for remote monitoring of physical activity in amyotrophic lateral sclerosis: a longitudinal cohort study.

    van Eijk, Ruben P A / Bakers, Jaap N E / Bunte, Tommy M / de Fockert, Arianne J / Eijkemans, Marinus J C / van den Berg, Leonard H

    Journal of neurology

    2019  Volume 266, Issue 10, Page(s) 2387–2395

    Abstract: Background: The extensive heterogeneity between patients with amyotrophic lateral sclerosis (ALS) complicates the quantification of disease progression. In this study, we determine the value of remote, accelerometer-based monitoring of physical activity ...

    Abstract Background: The extensive heterogeneity between patients with amyotrophic lateral sclerosis (ALS) complicates the quantification of disease progression. In this study, we determine the value of remote, accelerometer-based monitoring of physical activity in patients with ALS.
    Methods: This longitudinal cohort study was conducted in a home-based setting; all study materials were sent by mail. Patients wore the ActiGraph during waking hours for 7 days every 2-3 months and provided information regarding their daily functioning (ALSFRS-R). We defined four accelerometer-based endpoints that either reflect the average daily activity or quantify the patient's physical capacity.
    Results: A total of 42 patients participated; the total valid monitoring period was 9288 h with a 93.0% adherence rate. At baseline, patients were active 27.9% (range 11.6-52.4%) of their time; this declined by 0.64% (95% 0.43-0.86, p < 0.001) per month. Accelerometer-based endpoints were strongly associated with the ALSFRS-R (r 0.78, 95% CI 0.63-0.92, p < 0.001), but showed less variability over time than the ALSFRS-R (coefficient of variation 0.64-0.81 vs. 1.06, respectively). Accelerometer-based endpoints could reduce sample size by 30.3% for 12-month trials and 44.6% for 18-month trials; for trials lasting less than 9 months, the ALSFRS-R resulted in smaller sample sizes.
    Conclusion: Accelerometry is an objective method for quantifying disease progression, which could obtain real-world insights in the patient's physical functioning and may personalize the delivery of care. In addition, remote monitoring provides patients with the opportunity to participate in clinical trials from home, paving the way to a patient-centric clinical trial model.
    MeSH term(s) Accelerometry/standards ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis ; Amyotrophic Lateral Sclerosis/physiopathology ; Disease Progression ; Exercise/physiology ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Monitoring, Ambulatory/standards ; Reproducibility of Results
    Language English
    Publishing date 2019-06-11
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 187050-6
    ISSN 1432-1459 ; 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
    ISSN (online) 1432-1459
    ISSN 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
    DOI 10.1007/s00415-019-09427-5
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