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Design and initial results of a multi-phase randomized trial of ceftriaxone in amyotrophic lateral sclerosis

Berry, James D ; Shefner, Jeremy M ; Conwit, Robin ; Schoenfeld, David ; Keroack, Myles ; Felsenstein, Donna ; Krivickas, Lisa ; David, William S ; Vriesendorp, Francine ; Pestronk, Alan ; Caress, James B ; Katz, Jonathan ; Simpson, Ericka ; Rosenfeld, Jeffrey ; Pascuzzi, Robert ; Glass, Jonathan ; Rezania, Kourosh ; Rothstein, Jeffrey D ; Greenblatt, David J ; Cudkowicz, Merit E Forloni, Gianluigi

PloS one, 2013-04, Vol.8 (4), p.e61177 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Design and initial results of a multi-phase randomized trial of ceftriaxone in amyotrophic lateral sclerosis
Autor: Berry, James D ; Shefner, Jeremy M ; Conwit, Robin ; Schoenfeld, David ; Keroack, Myles ; Felsenstein, Donna ; Krivickas, Lisa ; David, William S ; Vriesendorp, Francine ; Pestronk, Alan ; Caress, James B ; Katz, Jonathan ; Simpson, Ericka ; Rosenfeld, Jeffrey ; Pascuzzi, Robert ; Glass, Jonathan ; Rezania, Kourosh ; Rothstein, Jeffrey D ; Greenblatt, David J ; Cudkowicz, Merit E
Forloni, Gianluigi
Assuntos: Amino acids ; Amyotrophic lateral sclerosis ; Amyotrophic Lateral Sclerosis - blood ; Amyotrophic Lateral Sclerosis - cerebrospinal fluid ; Amyotrophic Lateral Sclerosis - drug therapy ; Analysis ; Anti-Bacterial Agents - adverse effects ; Anti-Bacterial Agents - blood ; Anti-Bacterial Agents - pharmacokinetics ; Anti-Bacterial Agents - therapeutic use ; Antibiotics ; Ceftriaxone ; Ceftriaxone - adverse effects ; Ceftriaxone - blood ; Ceftriaxone - pharmacokinetics ; Ceftriaxone - therapeutic use ; Ceftriaxone sodium ; Cerebrospinal fluid ; Consortia ; Demography ; Disease ; Dosage ; Excitotoxicity ; Female ; Follow-Up Studies ; Glutamate ; Glutamic acid transporter ; Hospitals ; Humans ; Intravenous administration ; Male ; Mathematics ; Medical schools ; Medicine ; Middle Aged ; Multiple sclerosis ; Neurochemistry ; Neurology ; Neurons ; Neurosciences ; Pharmacokinetics ; Pharmacology ; Product development ; Research Design ; Reviews ; Rodents ; Safety ; Stroke ; Studies ; Test procedures ; Ursodeoxycholic acid ; Ursodiol
É parte de: PloS one, 2013-04, Vol.8 (4), p.e61177
Notas: Competing Interests: JDB has served as a consultant to Biogen Idec and as a paid speaker for Oakstone Publishing. He receives research report from the Muscular Dystrophy Association and ALS Therapy Alliance. JMS has served as a consultant to Biogen Idec, Cytokinetics, Trophos, ISIS, Glaxo Smith Kline, and receives research support from the Muscular Dystrophy Association, ALS Association, ALS Therapy Alliance, Cytokinetics, Biogen Idec, Sanofi Aventis, Neuraltus. RC is employed at the National Institute of Neurological Disorders and Stroke. DS, over the last 24 months, has served as a biostatistical consultant to Averion, Inc, Gerson Lehrman Group, Guidepoint Global, Neuronova, Cytokinetics, Glaxo Smith Kline, Merck, Aggennix, Pfizer, Biogen Idec, and Elan. He has received research support from AstraZeneca, Roche, CytRx, and ISIS. MK has no relevant disclosures to report. DF has received research funds from Euroimmune, Allere, Focus, Biokit, BioRad and Diasorin, Chronic Fatigue Initiative. LK has no relevant disclosures to report. WSD has no relevant disclosures to report. FV has no relevant disclosures to report. AP receives revenue related to antibody patent licenses from Athena; owns stock in Johnson & Johnson; directs the Washington University Neuromuscular Clinical Laboratory which performs antibody testing; and receives research support from the National Institutes of Health, Muscular Dystrophy Association, Neuromuscular Research Fund, Insmed, Knopp, Cytokinetics, Biogen Idec, ISIS, Genzyme, GSK, Ultragenyx & Sanofi. JBC has no relevant disclosures to report. JK has no relevant disclosures to report. ES has no relevant disclosures to report. JR has served on scientific advisory boards and/or as a consultant for Hill-ROM Inc, Cytokinetics and Avanir Pharmaceuticals. RP has no relevant disclosures to report. JG receives research support from the Muscular Dystrophy Association and from the National Institute of Neurological Disorders and Stroke. KR has no relevant disclosures to report. JR has research funding from National Institutes of Health, Department of Defense, P2ALS, Muscular Dystrophy Association, Robert Packard Center for ALS Research at Johns Hopkins. He has acted as a consultant to Biogen Idec, Cytokinetics and Psyadon Pharmaceuticals, Inc. DJG has no relevant disclosures to report. MEC served on DSMB for Synapse and Trophos and was a consultant for TEVA, Millenium, GlaxoSmithKline and Biogen. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
Members of the Northeast ALS Consortium are provided in File S1
Conceived and designed the experiments: JMS DS MK DF LK JR JDR DJG MEC. Performed the experiments: JDB JMS LK WSD FV AP JBC JK ES JR RP JG KR. Analyzed the data: JDB JMS RC DS MK DF JR JDR DJG MEC. Contributed reagents/materials/analysis tools: JMS DS JDR DJG. Wrote the paper: JDB JMS RC DS DF WSD FV AP JBC JK ES JR RP JG KR JDR DJG MEC. Study Supervision: JMS RC DS JDR MEC.
Descrição: Ceftriaxone increases expression of the astrocytic glutamate transporter, EAAT2, which might protect from glutamate-mediated excitotoxicity. A trial using a novel three stage nonstop design, incorporating Phases I-III, tested ceftriaxone in ALS. Stage 1 determined the cerebrospinal fluid pharmacokinetics of ceftriaxone in subjects with ALS. Stage 2 evaluated safety and tolerability for 20-weeks. Analysis of the pharmacokinetics, tolerability, and safety was used to determine the ceftriaxone dosage for Stage 3 efficacy testing. In Stage 1, 66 subjects at ten clinical sites were enrolled and randomized equally into three study groups receiving intravenous placebo, ceftriaxone 2 grams daily or ceftriaxone 4 grams daily divided BID. Participants provided serum and cerebrospinal fluid for pharmacokinetic analysis on study day 7. Participants continued their assigned treatment in Stage 2. The Data and Safety Monitoring Board (DSMB) reviewed the data after the last participants completed 20 weeks on study drug. Stage 1 analysis revealed linear pharmacokinetics, and CSF trough levels for both dosage levels exceeding the pre-specified target trough level of 1 µM (0.55 µg/mL). Tolerability (Stages 1 and 2) results showed that ceftriaxone at dosages up to 4 grams/day was well tolerated at 20 weeks. Biliary adverse events were more common with ceftriaxone but not dose-dependent and improved with ursodeoxycholic (ursodiol) therapy. The goals of Stages 1 and 2 of the ceftriaxone trial were successfully achieved. Based on the pre-specified decision rules, the DSMB recommended the use of ceftriaxone 4 g/d (divided BID) for Stage 3, which recently closed. ClinicalTrials.gov NCT00349622.
Editor: United States: Public Library of Science
Idioma: Inglês

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Design and initial results of a multi-phase randomized trial of ceftriaxone in amyotrophic lateral sclerosis

United States: Public Library of Science

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