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Clinical Trial
. 2013 Apr 17;8(4):e61177.
doi: 10.1371/journal.pone.0061177. Print 2013.

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

James D Berry  1 , Jeremy M Shefner, Robin Conwit, David Schoenfeld, Myles Keroack, Donna Felsenstein, Lisa Krivickas, William S David, Francine Vriesendorp, Alan Pestronk, James B Caress, Jonathan Katz, Ericka Simpson, Jeffrey Rosenfeld, Robert Pascuzzi, Jonathan Glass, Kourosh Rezania, Jeffrey D Rothstein, David J Greenblatt, Merit E Cudkowicz; Northeast ALS Consortium
Affiliations
Clinical Trial

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

James D Berry et al. PLoS One. .

Abstract

Objectives: 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.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1. Enrollment, Randomization, Follow-Up and Analysis.
Figure 2
Figure 2. Plasma and CSF Pharmacokinetics.
a. Mean and SE plasma ceftriaxone concentrations at corresponding times for both LD and HD arms. Levels are always higher with HD, relative to LD. b. Pre-dose (trough) plasma levels at Week 1 were highly correlated with the pre-dose levels at Week 4, indicating that steady-state had been reached by Week 1. Dashed line is the line of identity (y = x). c. Pre-dose CSF and plasma concentrations were significantly correlated using simple linear regression. The r-square value (0.54) indicates that plasma levels explain about 54% of variability in CSF levels. The slope of the regression line is about 0.04, indicating that CSF levels are much lower than plasma levels. Assuming that CSF uptake happens by passive diffusion, the difference is probably explained by plasma protein binding of ceftriaxone. d. Actual CSF concentrations, and the predicted “typical” concentration curves for the 2 gm/day and 4 gm/day dosage groups. Also shown is the boundary of 1.0 micromolar, equivalent to 0.55 µg/mL. This is the minimum effective concentration based on in vitro studies and the goal concentration for Stage 1.
Figure 3
Figure 3. Effect of Drug Holiday on CSF Drug Levels.
Predictive illustration of the effect of “drug holidays” at steady-state. Drug holiday began at the arrow (24 hours). Dosing then resumed as usual at 72 hours. Despite the holiday, CSF levels remained above 1 micromolar in the 4 gm/day group, and fell slightly below 1 micromolar in the 2 gm/day group.
Figure 4
Figure 4. Time to Discontinuation of Study Drug by Treatment Arm (until 20 weeks).
Kaplan-Meyer curve showing time to discontinuation of study drug within the first 20 weeks for patients who discontinued study drug within this time frame. Time to discontinuation of study drug was not significantly different between treatment arms (p = 0.90; Log-Rank). LD – Low Dose Ceftriaxone Arm; HD - High Dose Ceftriaxone Arm.
Figure 5
Figure 5. Cholelithiasis and Biliary Sludging by Treatment Arm.
(a) Biliary sludging and cholelithiasis were more common in the low dose (LD) and high dose (HD) treatment arms than in the placebo treatment arm (p<0.01; Jonckheere-Terpstra). (b) Treatment with ursodiol significantly shortened event duration when used to treat cholelithiasis and biliary sludging (p,0.001; Log-Rank).
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