[HTML][HTML] Design and initial results of a multi-phase randomized trial of ceftriaxone in amyotrophic lateral sclerosis
JD Berry, JM Shefner, R Conwit, D Schoenfeld… - PloS one, 2013 - journals.plos.org
JD Berry, JM Shefner, R Conwit, D Schoenfeld, M Keroack, D Felsenstein, L Krivickas…
PloS one, 2013•journals.plos.orgObjectives 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 …
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 …
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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