Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: Phase I single group and phase II randomized placebo-controlled studies.
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ABSTRACT:
SUBMITTER: Lovera J
PROVIDER: S-EPMC4675149 | biostudies-literature | 2015 Nov
REPOSITORIES: biostudies-literature
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Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: Phase I single group and phase II randomized placebo-controlled studies.
Lovera Jesus J Ramos Alexander A Devier Deidre D Garrison Virginia V Kovner Blake B Reza Tara T Koop Dennis D Rooney William W Foundas Anne A Bourdette Dennis D
Journal of the neurological sciences 20150807 1-2
<h4>Objectives</h4>Phase I (PhI): assess the safety of Polyphenon E in people with multiple sclerosis (MS) and determine the futility of Polyphenon E as a neuroprotective agent. Correlate plasma levels of EGCG with neuroprotective effects. Phase II (PhII): Further assess safety and confirm the neuroprotective effects of Polyphenon E.<h4>Design</h4>PhI: single group futility study. PhII: parallel group randomized double-blind placebo-controlled study.<h4>Participants</h4>Recruitment area (both st ...[more]
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Project description:IntroductionAmyotrophic lateral sclerosis (ALS) is a fatal progressive neurological disorder characterised by a selective degeneration of motor neurons (MNs). Stem cell transplantation is considered as a promising strategy in neurological disorders therapy and the possibility of inducing bone marrow cells (BMCs) to circulate in the peripheral blood is suggested to investigate stem cells migration in degenerated ALS nerve tissues where potentially repair MN damage. Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates haematopoietic progenitor cells, mobilises BMCs into injured brain and it is itself a neurotrophic factor for MN. G-CSF safety in humans has been demonstrated and many observations suggest that it may affect neural cells. Therefore, we decided to use G-CSF to mobilise BMCs into the peripheral circulation in patients with ALS, planning a clinical trial to evaluate the effect of G-CSF administration in ALS patients compared with placebo.Methods and analysisSTEMALS-II is a phase II multicentre, randomised double-blind, placebo-controlled, parallel group clinical trial on G-CSF (filgrastim) and mannitol in ALS patients. Specifically, we investigate safety, tolerability and efficacy of four repeated courses of intravenous G-CSF and mannitol administered in 76 ALS patients in comparison with placebo (indistinguishable glucose solution 5%). We determine increase of G-CSF levels in serum and cerebrospinal fluid as CD34+ cells and leucocyte count after treatment; reduction in ALS Functional Rating Scale-Revised Score, forced vital capacity, Scale for Testing Muscle Strength Score and quality of life; the adverse events/reactions during the treatment; changes in neuroinflammation biomarkers before and after treatment.Ethics and disseminationThe study protocol was approved by the Ethics Committee of Azienda Ospedaliera Universitaria 'Città della Salute e della Scienza', Torino, Italy. Results will be presented during scientific symposia or published in scientific journals.Trial registration numberEudract 2014-002228-28.
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Project description:OBJECTIVE:To evaluate the efficacy and safety of oral levosimendan in patients with amyotrophic lateral sclerosis (ALS). This phase II, randomised, double-blind, placebo-controlled, crossover, three-period study with 6 months open-label follow-up enrolled adults with ALS and sitting slow vital capacity (SVC) 60%-90 % of predicted from 11 sites in four countries. METHODS:Patients received levosimendan 1?mg daily, 1?mg two times a day or placebo during three 14-day crossover periods and levosimendan 1-2?mg daily during open-label follow-up. Primary endpoint was sitting SVC; secondary endpoints included supine SVC, ALS Functional Rating Scale-Revised (ALSFRS-R), tolerability and safety. RESULTS:Of 66 patients randomised, 59 contributed to the double-blind results and 50 entered open-label follow-up. Sitting SVC was not significantly different between the treatments. In post hoc analysis using period-wise baselines, supine SVC favoured levosimendan over placebo, estimated mean differences from baseline being -3.62% on placebo, +0.77% on levosimendan 1?mg daily (p=0.018) and +2.38% on 1?mg two times a day (p=0.001). Headache occurred in 16.7% of patients during levosimendan 1?mg daily (p=0.030), 28.6% during 1?mg two times a day (p=0.002) and 3.3% during placebo. The respective frequencies for increased heart rate were 5.1% (p=0.337), 18.5% (p=0.018) and 1.7%. No significant differences between the treatments were seen for other adverse events. CONCLUSIONS:Levosimendan did not achieve the primary endpoint of improving sitting SVC in ALS. Headache and increased heart rate were increased on levosimendan, although it was otherwise well tolerated. A phase III study to evaluate the longer term effects of oral levosimendan in ALS is ongoing.
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Project description:BACKGROUND:Placebo beverage conditions remain a key element in the methodological toolkit for alcohol researchers interested in evaluating pharmacological and nonpharmacological factors influencing the effects of alcohol consumption. While interest in experimentally examining alcohol in social context is on the rise, there has been little research examining the effectiveness of placebo manipulations in group settings, when just 1 suspicious participant could potentially jeopardize the effect of the placebo on group members. Moreover, research has rarely considered the association between individual difference factors (e.g., gender) and placebo manipulation effectiveness. The present study, using an uncommonly large sample of placebo-consuming participants, was well suited to investigate fundamental questions regarding placebo efficacy that have not been assessed previously. Specifically, we aimed to examine placebo efficacy and general processes of placebo functioning in a group context. We also assessed potential associations between a variety of individual difference factors and placebo response. METHODS:A total of 240 participants (50% male) consumed placebo beverages during a triadic drinking period (across 80 three-person groups). Participants reported their subjective intoxication, stimulation, and sedation 8 minutes following drink consumption and estimated the alcohol content of their drink at the end of the study. RESULTS:Participants consuming placebo beverages in groups were nearly universal in reporting that they had consumed alcohol (>99%) and had experienced an increase in feelings of intoxication [t(239) = 22.03, p < 0.001] and stimulation [t(239) = 5.53, p < 0.001], levels that were similar to those observed in prior studies conducted with participants drinking placebos in isolation. Further, participants' placebo responses were independent of their 2 group members and were largely unaffected by a variety of individual difference factors. CONCLUSIONS:Placebo response generally operated independently of group-member influences, suggesting that researchers can successfully conduct placebo beverage studies utilizing group drinking designs.
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Project description:Background and purposeAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials.MethodsThis was a phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial. Participants diagnosed with definite, probable or probable laboratory-supported ALS were assigned to receive RNS60 or placebo administered for 24 weeks intravenously (375 ml) once a week and via nebulization (4 ml/day) on non-infusion days, followed by an additional 24 weeks off-treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale-Revised), a measure of self-sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire-40, ALSAQ-40) and survival. Tolerability and safety were assessed.ResultsSeventy-four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ-40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, p = 0.0101; ALSAQ-40, difference -0.19 per week, standard error 0.10, p = 0.0319). Adverse events were similar in the two arms. In a post hoc analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60.ConclusionsThe positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation.
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