BACKGROUND: Glutamate excitotoxicity might contribute to the pathophysiology of 
amyotrophic lateral sclerosis. In animal models, decreased excitatory aminoacid 
transporter 2 (EAAT2) overexpression delays disease onset and prolongs survival, 
and ceftriaxone increases EAAT2 activity. We aimed to assess the safety and 
efficacy of ceftriaxone for amyotrophic lateral sclerosis in a combined phase 1, 
2, and 3 clinical trial.
METHODS: This three-stage randomised, double-blind, placebo-controlled study was 
done at 59 clinical sites in the USA and Canada between Sept 4, 2006, and July 
30, 2012. Eligible adult patients had amyotrophic lateral sclerosis, a vital 
capacity of more than 60% of that predicted for age and height, and symptom 
duration of less than 3 years. In stages 1 (pharmacokinetics) and 2 (safety), 
participants were randomly allocated (2:1) to ceftriaxone (2 g or 4 g per day) 
or placebo. In stage 3 (efficacy), participants assigned to ceftriaxone in stage 
2 received 4 g ceftriaxone, participants assigned to placebo in stage 2 received 
placebo, and new participants were randomly assigned (2:1) to 4 g ceftriaxone or 
placebo. Participants, family members, and site staff were masked to treatment 
assignment. Randomisation was done by a computerised randomisation sequence with 
permuted blocks of 3. Participants received 2 g ceftriaxone or placebo twice 
daily through a central venous catheter administered at home by a trained 
caregiver. To minimise biliary side-effects, participants assigned to 
ceftriaxone also received 300 mg ursodeoxycholic acid twice daily and those 
assigned to placebo received matched placebo capsules. The coprimary efficacy 
outcomes were survival and functional decline, measured as the slope of 
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. 
Analyses were by intention to treat. This study is registered with 
ClinicalTrials.gov, number NCT00349622.
FINDINGS: Stage 3 included 66 participants from stages 1 and 2 and 448 new 
participants. In total, 340 participants were randomly allocated to ceftriaxone 
and 173 to placebo. During stages 1 and 2, mean ALSFRS-R declined more slowly in 
participants who received 4 g ceftriaxone than in those on placebo (difference 
0·51 units per month, 95% CI 0·02 to 1·00; p=0·0416), but in stage 3 functional 
decline between the treatment groups did not differ (0·09, -0·06 to 0·24; 
p=0·2370). No significant differences in survival between the groups were 
recorded in stage 3 (HR 0·90, 95% CI 0·71 to 1·15; p=0·4146). Gastrointestinal 
adverse events and hepatobiliary adverse events were more common in the 
ceftriaxone group than in the placebo group (gastrointestinal, 245 of 340 [72%] 
ceftriaxone vs 97 of 173 [56%] placebo, p=0·0004; hepatobiliary, 211 [62%] vs 19 
[11%], p<0·0001). Significantly more participants who received ceftriaxone had 
serious hepatobiliary serious adverse events (41 participants [12%]) than did 
those who received placebo (0 participants).
INTERPRETATION: Despite promising stage 2 data, stage 3 of this trial of 
ceftriaxone in amyotrophic lateral sclerosis did not show clinical efficacy. The 
adaptive design allowed for seamless transition from one phase to another, and 
central venous catheter use in the home setting was shown to be feasible.
FUNDING: National Institute of Neurological Disorders and Stroke.