Journal
PLOS ONE
Volume 8, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0061177
Keywords
-
Categories
Funding
- National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health [U01 NS049640-05]
- Institute of Clinical and Translational Sciences [UL1 TR000448]
- Muscular Dystrophy Association
- ALS Association
- ALS Therapy Alliance
- Cytokinetics
- Biogen Idec
- Sanofi Aventis
- Neuraltus
- AstraZeneca
- Roche
- CytRx
- ISIS
- Euroimmune
- Allere
- Focus
- Biokit
- BioRad
- Diasorin
- Chronic Fatigue Initiative
- National Institutes of Health
- Neuromuscular Research Fund
- Insmed
- Knopp
- Genzyme
- GSK
- Ultragenyx Sanofi
- National Institute of Neurological Disorders and Stroke
- Department of Defense
- P2ALS
- Robert Packard Center for ALS Research at Johns Hopkins
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000448] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [U01NS049640] Funding Source: NIH RePORTER
Ask authors/readers for more resources
Objective: 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 mu M (0.55 mu g/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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available