Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1083-1091 |
| Number of pages | 9 |
| Journal | The Lancet Neurology |
| Volume | 13 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2014 |
Bibliographical note
Publisher Copyright:© 2014 Elsevier Ltd.
Funding
This trial was funded by the National Institute of Neurological Disorders and Stroke (grant 5 U01-NS-049640). Editorial support for the writing of this paper was funded by an anonymous philanthropic gift to the Massachusetts General Hospital (Boston, MA, USA) amyotrophic lateral sclerosis programme. Linda Goldstein from Excel Scientific Solutions (Southport, CT, USA) wrote the first draft of the report based on input from the authors, and Joanne King from Excel Scientific Solutions copyedited and styled the report per journal requirements. We thank the study participants and their families; Carl Leventhal for serving as the medical monitor; and Mary Lou Watson and her colleagues Meghan Hall, Cory Dauphin, Timothy Patrick, Sean Gray, Joseph Thomas, Nazanin Khajouee Nejad, and Dafna Rebibo from the Outcomes Centre at the State University of New York (NY, USA) for providing the study monitoring and outcomes training. We also thank the Neurological Clinical Research Institute project managers Julie Berkley, Kathryn Delaney, Lauren Mazzapica, Jane McKinley (Canadian ALS Research Network manager), and Amy Swartz; data managers Jing Deng, Haining Li, and Eric Tustison; systems managers Igor Katsovskiy, Roger Selsov, Ervin Sinani, Jason Walker, and Karen Wallace; grants manager Bryan Sweet; administrative staff Nicole Day and Francine Murphy; John Vetrano from the central pharmacy at Massachusetts General Hospital; and Scott Walker from the central pharmacy at Sunnybrook Medical Centre (Toronto, Canada). MEC has served as consultant to GlaxoSmithKline, Shire, and Teva and was a member of a data safety monitoring board for Synapse and Trophos. DS has received grants from the National Institutes of Health (NIH), Isis Pharmaceuticals, Prize for Life, Immunosuppression (Research Sundry Fund), ALS Therapy Development Institute, Diaphragm Pacing Study (SUNY Subaward), ALS Therapy Alliance–Selection Design, and Mexilitine (Research Sundry Fund), and personal fees from Neuronova. BB has received grants from the ALS Association, ALS Therapy Alliance, Carolinas ALS Research Fund, Heineman Medical Research Fund, Johns Hopkins University School of Medicine, Muscular Dystrophy Association, and the National Institute of Neurological Disorders and Stroke (NINDS), and educational grants from the Carolinas Healthcare Foundation and Knopp Biosciences for the North American ALS Research Group (ALSRG) Conferences at the 2012 and 2013 ALS–MND symposia; has served as a scientific adviser or consultant for Asubio, Biogen Idec, Bristol-Myers Squibb, Cytokinetic, Countervail Corp, Knopp Biosciences, Nova Biomedical, and NeuroDyn; has served on the board of directors for ALSRG, as a co-chairman or member of the American Academy of Neurology (AAN) Task Force on ALS Quality Measures, Development of AAN Registry, and as a member of the Centers for Disease Control and Prevention's Agency for Toxic Substances and Disease Registry/National ALS Registry Oversight Committee; and was an invited speaker at Knopp Biosciences' Symposium in 2013, and Biogen Idec/Knopp Biosciences' Symposium in 2012. DF received grants from the NINDS during the study. DJG received grants from the NIH during the study. JR has received research support from the Hill Rom Corporation, Cytokinetics, Biogen, and the Central California Faculty Medical Group, and has served as a scientific adviser for the Hill Rom Corporation during the study and development of the report; none of these overlapped with the scope of the ceftriaxone project. JDR received grants from the ALS Association, Muscular Dystrophy Association, NIH, and P2ALS, and served as a consultant for Ruxton/Psyadon Pharmaceuticals during the study; he received consultancy fees from Cytokenetics and has unlicensed patents on the use of drugs (not ceftriaxone) to modulate EAAT2 as a therapy outside the submitted work. JMS received grants from the NIH during the study; grants and personal fees from Biogen Idec, Cytokinetics, GlaxoSmithKline, and Isis Pharmaceuticals; grants from Sanofi-Aventis; and personal fees from Synaerion, Trophos, and UpToDate outside the submitted work. RC was a NINDS member of the study steering committee and took part in discussions about study interpretation. DH, MaK, MyK, JTK, RM, AlS, AmS, ES, ST, NT-R, HY, and LZ declare no competing interests.
| Funders | Funder number |
|---|---|
| Heineman Medical Research Fund | |
| Johns Hopkins University School of Medicine, Muscular Dystrophy Association | |
| Knopp Biosciences LLC | |
| Neurodyn Inc. | |
| National Institutes of Health (NIH) | |
| National Institute of Neurological Disorders and Stroke | U01NS049640 |
| Hennepin Faculty Associates Amyotrophic Lateral Sclerosis Association Certified ALS Center | |
| ALS Therapy Development Institute | |
| American Academy of Neurology | |
| Carolinas HealthCare Foundation |
ASJC Scopus subject areas
- Clinical Neurology