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dc.contributor.authorBerry, James Dale
dc.contributor.authorShefner, Jeremy M.
dc.contributor.authorConwit, Robin
dc.contributor.authorSchoenfeld, David Alan
dc.contributor.authorKeroack, Myles
dc.contributor.authorFelsenstein, Donna
dc.contributor.authorKrivickas, Lisa
dc.contributor.authorDavid, William Samuel
dc.contributor.authorVriesendorp, Francine
dc.contributor.authorPestronk, Alan
dc.contributor.authorCaress, James B.
dc.contributor.authorKatz, Jonathan
dc.contributor.authorSimpson, Ericka
dc.contributor.authorRosenfeld, Jeffrey
dc.contributor.authorPascuzzi, Robert
dc.contributor.authorGlass, Jonathan
dc.contributor.authorRezania, Kourosh
dc.contributor.authorRothstein, Jeffrey D.
dc.contributor.authorGreenblatt, David J.
dc.contributor.authorCudkowicz, Merit Ester
dc.date.accessioned2013-10-17T16:52:40Z
dc.date.issued2013
dc.identifier.citationBerry, James D., Jeremy M. Shefner, Robin Conwit, David Schoenfeld, Myles Keroack, Donna Felsenstein, Lisa Krivickas, et al. 2013. Design and initial results of a multi-phase randomized trial of ceftriaxone in amyotrophic lateral sclerosis. PLoS ONE 8(4): e61177.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11180990
dc.description.abstractObjectives: 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. Methods: 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. Results: 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. Conclusions: 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. Trial Registration ClinicalTrials.gov NCT00349622.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pone.0061177en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629222/pdf/en_US
dash.licenseLAA
dc.subjectMathematicsen_US
dc.subjectStatisticsen_US
dc.subjectBiostatisticsen_US
dc.subjectMedicineen_US
dc.subjectClinical Research Designen_US
dc.subjectClinical Trialsen_US
dc.subjectPhase Ien_US
dc.subjectPhase IIen_US
dc.subjectDrugs and Devicesen_US
dc.subjectPharmacokineticsen_US
dc.subjectNeurologyen_US
dc.subjectMotor Neuron Diseasesen_US
dc.subjectAmyotrophic Lateral Sclerosisen_US
dc.subjectNeurodegenerative Diseasesen_US
dc.titleDesign and Initial Results of a Multi-Phase Randomized Trial of Ceftriaxone in Amyotrophic Lateral Sclerosisen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorBerry, James Dale
dc.date.available2013-10-17T16:52:40Z
dc.identifier.doi10.1371/journal.pone.0061177*
dash.authorsorderedfalse
dash.contributor.affiliatedBerry, James
dash.contributor.affiliatedFelsenstein, Donna
dash.contributor.affiliatedDavid, William
dash.contributor.affiliatedCudkowicz, Merit
dash.contributor.affiliatedSchoenfeld, David


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