title: Design and initial results of a multi-phase randomized trial of ceftriaxone in amyotrophic lateral sclerosis.
abstract: 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 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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00349622.
authors.affiliation: Neurology Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: James D
authors.initials: JD
authors.lastname: Berry
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Shefner
authors.forename: Robin
authors.initials: R
authors.lastname: Conwit
authors.forename: David
authors.initials: D
authors.lastname: Schoenfeld
authors.forename: Myles
authors.initials: M
authors.lastname: Keroack
authors.forename: Donna
authors.initials: D
authors.lastname: Felsenstein
authors.forename: Lisa
authors.initials: L
authors.lastname: Krivickas
authors.forename: William S
authors.initials: WS
authors.lastname: David
authors.forename: Francine
authors.initials: F
authors.lastname: Vriesendorp
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.forename: James B
authors.initials: JB
authors.lastname: Caress
authors.forename: Jonathan
authors.initials: J
authors.lastname: Katz
authors.forename: Ericka
authors.initials: E
authors.lastname: Simpson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rosenfeld
authors.forename: Robert
authors.initials: R
authors.lastname: Pascuzzi
authors.forename: Jonathan
authors.initials: J
authors.lastname: Glass
authors.forename: Kourosh
authors.initials: K
authors.lastname: Rezania
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Rothstein
authors.forename: David J
authors.initials: DJ
authors.lastname: Greenblatt
authors.forename: Merit E
authors.initials: ME
authors.lastname: Cudkowicz
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002443:Ceftriaxone / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003710:Demography; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D012107:Research Design
chemical_list: D000900:Anti-Bacterial Agents; D002443:Ceftriaxone