Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: A multi-stage, randomised, double-blind, placebo-controlled trial

Merit E. Cudkowicz, Sarah Titus, Marianne Kearney, Hong Yu, Alexander Sherman, David Schoenfeld, Douglas Hayden, Amy Shui, Benjamin Brooks, Robin Conwit, Donna Felsenstein, David J. Greenblatt, Myles Keroack, John T. Kissel, Robert Miller, Jeffrey Rosenfeld, Jeffrey D. Rothstein, Ericka Simpson, Nina Tolkoff-Rubin, Lorne ZinmanJeremy M. Shefner, S. Kalra, L. Korngut, H. Omar-Crawford, R. Sekhon, C. White, T. Benstead, I. Grant, S. Reidy, C. McIntosh, J. McKinley, C. Shoesmith, L. Zinman, S. Botez, J. P. Bouchard, M. D'Amour, A. Genge, N. Hank, T. Levine, D. Saperstein, R. Alvarez, C. Banda, R. Garcia, M. Graves, H. Gruendler, J. Katz, F. Lin, C. Lomen-Hoerth, V. Martin, R. Miller, D. Moses, T. Mozaffar, L. Nist, B. Oskarsson, J. Rosenfeld, E. Tsimerinov, P. Tully, C. Villierme, K. Voelz, M. Wiedau-Pazos, Y. Rollins, K. Felice, E. Bayat, A. N. Kelly, K. B. Boylan, P. DeSaro, D. Koggan, A. Verma, J. Bordeau, J. Glass, M. Polak, B. Quarles, M. H. Rivner, P. Casey, R. Sufit, C. Bodkin, S. Guingrich, J. Kincaid, A. Micheels, R. Pascuzzi, R. Snook, R. J. Barohn, A. Dick, L. Herbelin, M. M. Dimachkie, A. L. McVey, M. Walsh, Y. Wang, J. Hutchison, E. Kasarskis, J. King, T. Tandy, S. Thomas, K. Vanderpool, J. Rothstein, P. Andres, M. Bellanich, M. E. Cudkowicz, W. David, A. Goldenberg, D. J. Greenblatt, L. Krivickas, L. Loci, M. Majkut, O. O'Connor, M. Parkinson, D. Pulley, J. Russell, L. Sullivan, H. Foley, D. Gelinas, D. S. Newman, S. Bundlie, T. Leviton, S. Patel, C. Rohde, S. Swanson, E. Tiryaki, A. Fann, G. Hayat, A. Pestronk, G. L. Pattee, B. Weber, M. Keroack, B. Belsh, J. Belsh, M. A. Mertz, A. M. DeNero, T. Imperato, D. J. Lange, N. Kassebaum, D. MacGowan, H. Mitsumoto, S. N. Scelsa, M. Shahbazi, J. M. Shefner, L. Simionescu, M. L. Watson, J. Wymer, E. Bravver, B. R. Brooks, J. Caress, M. S. Cartwright, T. Johnston-Crews, C. Lary, J. Shuh, A. Bartlett, N. Berry, J. T. Kissel, R. Kuenzler, E. P. Pioro, A. Quick, B. Ash, K. Goslin, A. Deboo, A. Giampole, T. Heiman-Patterson, D. Lacomis, L. McCluskey, M. Powell, S. Rana, L. Rojas, D. Rowlands, Z. Simmons, H. E. Stephens, M. DeCandio, D. Stickler, D. L. Davis, P. D. Donofrio, S. Halton, S. Hand, M. Hastings, D. Heitzman, L. Lay, J. McCloskey, E. Simpson, M. Bromberg, A. Joshi, L. H. Phillips

Research output: Contribution to journalArticle

91 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1083-1091
Number of pages9
JournalThe Lancet Neurology
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2014
Externally publishedYes

Fingerprint

Ceftriaxone
Amyotrophic Lateral Sclerosis
Placebos
Safety
Central Venous Catheters
Random Allocation
Survival
National Institute of Neurological Disorders and Stroke
Ursodeoxycholic Acid
Phase III Clinical Trials
Clinical Trials, Phase I
Intention to Treat Analysis
Phase Transition
Vital Capacity
Caregivers
Canada
Capsules
Glutamic Acid

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis : A multi-stage, randomised, double-blind, placebo-controlled trial. / Cudkowicz, Merit E.; Titus, Sarah; Kearney, Marianne; Yu, Hong; Sherman, Alexander; Schoenfeld, David; Hayden, Douglas; Shui, Amy; Brooks, Benjamin; Conwit, Robin; Felsenstein, Donna; Greenblatt, David J.; Keroack, Myles; Kissel, John T.; Miller, Robert; Rosenfeld, Jeffrey; Rothstein, Jeffrey D.; Simpson, Ericka; Tolkoff-Rubin, Nina; Zinman, Lorne; Shefner, Jeremy M.; Kalra, S.; Korngut, L.; Omar-Crawford, H.; Sekhon, R.; White, C.; Benstead, T.; Grant, I.; Reidy, S.; McIntosh, C.; McKinley, J.; Shoesmith, C.; Zinman, L.; Botez, S.; Bouchard, J. P.; D'Amour, M.; Genge, A.; Hank, N.; Levine, T.; Saperstein, D.; Alvarez, R.; Banda, C.; Garcia, R.; Graves, M.; Gruendler, H.; Katz, J.; Lin, F.; Lomen-Hoerth, C.; Martin, V.; Miller, R.; Moses, D.; Mozaffar, T.; Nist, L.; Oskarsson, B.; Rosenfeld, J.; Tsimerinov, E.; Tully, P.; Villierme, C.; Voelz, K.; Wiedau-Pazos, M.; Rollins, Y.; Felice, K.; Bayat, E.; Kelly, A. N.; Boylan, K. B.; DeSaro, P.; Koggan, D.; Verma, A.; Bordeau, J.; Glass, J.; Polak, M.; Quarles, B.; Rivner, M. H.; Casey, P.; Sufit, R.; Bodkin, C.; Guingrich, S.; Kincaid, J.; Micheels, A.; Pascuzzi, R.; Snook, R.; Barohn, R. J.; Dick, A.; Herbelin, L.; Dimachkie, M. M.; McVey, A. L.; Walsh, M.; Wang, Y.; Hutchison, J.; Kasarskis, E.; King, J.; Tandy, T.; Thomas, S.; Vanderpool, K.; Rothstein, J.; Andres, P.; Bellanich, M.; Cudkowicz, M. E.; David, W.; Goldenberg, A.; Greenblatt, D. J.; Krivickas, L.; Loci, L.; Majkut, M.; O'Connor, O.; Parkinson, M.; Pulley, D.; Russell, J.; Sullivan, L.; Foley, H.; Gelinas, D.; Newman, D. S.; Bundlie, S.; Leviton, T.; Patel, S.; Rohde, C.; Swanson, S.; Tiryaki, E.; Fann, A.; Hayat, G.; Pestronk, A.; Pattee, G. L.; Weber, B.; Keroack, M.; Belsh, B.; Belsh, J.; Mertz, M. A.; DeNero, A. M.; Imperato, T.; Lange, D. J.; Kassebaum, N.; MacGowan, D.; Mitsumoto, H.; Scelsa, S. N.; Shahbazi, M.; Shefner, J. M.; Simionescu, L.; Watson, M. L.; Wymer, J.; Bravver, E.; Brooks, B. R.; Caress, J.; Cartwright, M. S.; Johnston-Crews, T.; Lary, C.; Shuh, J.; Bartlett, A.; Berry, N.; Kissel, J. T.; Kuenzler, R.; Pioro, E. P.; Quick, A.; Ash, B.; Goslin, K.; Deboo, A.; Giampole, A.; Heiman-Patterson, T.; Lacomis, D.; McCluskey, L.; Powell, M.; Rana, S.; Rojas, L.; Rowlands, D.; Simmons, Z.; Stephens, H. E.; DeCandio, M.; Stickler, D.; Davis, D. L.; Donofrio, P. D.; Halton, S.; Hand, S.; Hastings, M.; Heitzman, D.; Lay, L.; McCloskey, J.; Simpson, E.; Bromberg, M.; Joshi, A.; Phillips, L. H.

In: The Lancet Neurology, Vol. 13, No. 11, 01.11.2014, p. 1083-1091.

Research output: Contribution to journalArticle

Cudkowicz, ME, Titus, S, Kearney, M, Yu, H, Sherman, A, Schoenfeld, D, Hayden, D, Shui, A, Brooks, B, Conwit, R, Felsenstein, D, Greenblatt, DJ, Keroack, M, Kissel, JT, Miller, R, Rosenfeld, J, Rothstein, JD, Simpson, E, Tolkoff-Rubin, N, Zinman, L, Shefner, JM, Kalra, S, Korngut, L, Omar-Crawford, H, Sekhon, R, White, C, Benstead, T, Grant, I, Reidy, S, McIntosh, C, McKinley, J, Shoesmith, C, Zinman, L, Botez, S, Bouchard, JP, D'Amour, M, Genge, A, Hank, N, Levine, T, Saperstein, D, Alvarez, R, Banda, C, Garcia, R, Graves, M, Gruendler, H, Katz, J, Lin, F, Lomen-Hoerth, C, Martin, V, Miller, R, Moses, D, Mozaffar, T, Nist, L, Oskarsson, B, Rosenfeld, J, Tsimerinov, E, Tully, P, Villierme, C, Voelz, K, Wiedau-Pazos, M, Rollins, Y, Felice, K, Bayat, E, Kelly, AN, Boylan, KB, DeSaro, P, Koggan, D, Verma, A, Bordeau, J, Glass, J, Polak, M, Quarles, B, Rivner, MH, Casey, P, Sufit, R, Bodkin, C, Guingrich, S, Kincaid, J, Micheels, A, Pascuzzi, R, Snook, R, Barohn, RJ, Dick, A, Herbelin, L, Dimachkie, MM, McVey, AL, Walsh, M, Wang, Y, Hutchison, J, Kasarskis, E, King, J, Tandy, T, Thomas, S, Vanderpool, K, Rothstein, J, Andres, P, Bellanich, M, Cudkowicz, ME, David, W, Goldenberg, A, Greenblatt, DJ, Krivickas, L, Loci, L, Majkut, M, O'Connor, O, Parkinson, M, Pulley, D, Russell, J, Sullivan, L, Foley, H, Gelinas, D, Newman, DS, Bundlie, S, Leviton, T, Patel, S, Rohde, C, Swanson, S, Tiryaki, E, Fann, A, Hayat, G, Pestronk, A, Pattee, GL, Weber, B, Keroack, M, Belsh, B, Belsh, J, Mertz, MA, DeNero, AM, Imperato, T, Lange, DJ, Kassebaum, N, MacGowan, D, Mitsumoto, H, Scelsa, SN, Shahbazi, M, Shefner, JM, Simionescu, L, Watson, ML, Wymer, J, Bravver, E, Brooks, BR, Caress, J, Cartwright, MS, Johnston-Crews, T, Lary, C, Shuh, J, Bartlett, A, Berry, N, Kissel, JT, Kuenzler, R, Pioro, EP, Quick, A, Ash, B, Goslin, K, Deboo, A, Giampole, A, Heiman-Patterson, T, Lacomis, D, McCluskey, L, Powell, M, Rana, S, Rojas, L, Rowlands, D, Simmons, Z, Stephens, HE, DeCandio, M, Stickler, D, Davis, DL, Donofrio, PD, Halton, S, Hand, S, Hastings, M, Heitzman, D, Lay, L, McCloskey, J, Simpson, E, Bromberg, M, Joshi, A & Phillips, LH 2014, 'Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: A multi-stage, randomised, double-blind, placebo-controlled trial', The Lancet Neurology, vol. 13, no. 11, pp. 1083-1091. https://doi.org/10.1016/S1474-4422(14)70222-4
Cudkowicz, Merit E. ; Titus, Sarah ; Kearney, Marianne ; Yu, Hong ; Sherman, Alexander ; Schoenfeld, David ; Hayden, Douglas ; Shui, Amy ; Brooks, Benjamin ; Conwit, Robin ; Felsenstein, Donna ; Greenblatt, David J. ; Keroack, Myles ; Kissel, John T. ; Miller, Robert ; Rosenfeld, Jeffrey ; Rothstein, Jeffrey D. ; Simpson, Ericka ; Tolkoff-Rubin, Nina ; Zinman, Lorne ; Shefner, Jeremy M. ; Kalra, S. ; Korngut, L. ; Omar-Crawford, H. ; Sekhon, R. ; White, C. ; Benstead, T. ; Grant, I. ; Reidy, S. ; McIntosh, C. ; McKinley, J. ; Shoesmith, C. ; Zinman, L. ; Botez, S. ; Bouchard, J. P. ; D'Amour, M. ; Genge, A. ; Hank, N. ; Levine, T. ; Saperstein, D. ; Alvarez, R. ; Banda, C. ; Garcia, R. ; Graves, M. ; Gruendler, H. ; Katz, J. ; Lin, F. ; Lomen-Hoerth, C. ; Martin, V. ; Miller, R. ; Moses, D. ; Mozaffar, T. ; Nist, L. ; Oskarsson, B. ; Rosenfeld, J. ; Tsimerinov, E. ; Tully, P. ; Villierme, C. ; Voelz, K. ; Wiedau-Pazos, M. ; Rollins, Y. ; Felice, K. ; Bayat, E. ; Kelly, A. N. ; Boylan, K. B. ; DeSaro, P. ; Koggan, D. ; Verma, A. ; Bordeau, J. ; Glass, J. ; Polak, M. ; Quarles, B. ; Rivner, M. H. ; Casey, P. ; Sufit, R. ; Bodkin, C. ; Guingrich, S. ; Kincaid, J. ; Micheels, A. ; Pascuzzi, R. ; Snook, R. ; Barohn, R. J. ; Dick, A. ; Herbelin, L. ; Dimachkie, M. M. ; McVey, A. L. ; Walsh, M. ; Wang, Y. ; Hutchison, J. ; Kasarskis, E. ; King, J. ; Tandy, T. ; Thomas, S. ; Vanderpool, K. ; Rothstein, J. ; Andres, P. ; Bellanich, M. ; Cudkowicz, M. E. ; David, W. ; Goldenberg, A. ; Greenblatt, D. J. ; Krivickas, L. ; Loci, L. ; Majkut, M. ; O'Connor, O. ; Parkinson, M. ; Pulley, D. ; Russell, J. ; Sullivan, L. ; Foley, H. ; Gelinas, D. ; Newman, D. S. ; Bundlie, S. ; Leviton, T. ; Patel, S. ; Rohde, C. ; Swanson, S. ; Tiryaki, E. ; Fann, A. ; Hayat, G. ; Pestronk, A. ; Pattee, G. L. ; Weber, B. ; Keroack, M. ; Belsh, B. ; Belsh, J. ; Mertz, M. A. ; DeNero, A. M. ; Imperato, T. ; Lange, D. J. ; Kassebaum, N. ; MacGowan, D. ; Mitsumoto, H. ; Scelsa, S. N. ; Shahbazi, M. ; Shefner, J. M. ; Simionescu, L. ; Watson, M. L. ; Wymer, J. ; Bravver, E. ; Brooks, B. R. ; Caress, J. ; Cartwright, M. S. ; Johnston-Crews, T. ; Lary, C. ; Shuh, J. ; Bartlett, A. ; Berry, N. ; Kissel, J. T. ; Kuenzler, R. ; Pioro, E. P. ; Quick, A. ; Ash, B. ; Goslin, K. ; Deboo, A. ; Giampole, A. ; Heiman-Patterson, T. ; Lacomis, D. ; McCluskey, L. ; Powell, M. ; Rana, S. ; Rojas, L. ; Rowlands, D. ; Simmons, Z. ; Stephens, H. E. ; DeCandio, M. ; Stickler, D. ; Davis, D. L. ; Donofrio, P. D. ; Halton, S. ; Hand, S. ; Hastings, M. ; Heitzman, D. ; Lay, L. ; McCloskey, J. ; Simpson, E. ; Bromberg, M. ; Joshi, A. ; Phillips, L. H. / Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis : A multi-stage, randomised, double-blind, placebo-controlled trial. In: The Lancet Neurology. 2014 ; Vol. 13, No. 11. pp. 1083-1091.
@article{cef2bf880b494e778c8156b23961d962,
title = "Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: A multi-stage, randomised, double-blind, placebo-controlled trial",
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.",
author = "Cudkowicz, {Merit E.} and Sarah Titus and Marianne Kearney and Hong Yu and Alexander Sherman and David Schoenfeld and Douglas Hayden and Amy Shui and Benjamin Brooks and Robin Conwit and Donna Felsenstein and Greenblatt, {David J.} and Myles Keroack and Kissel, {John T.} and Robert Miller and Jeffrey Rosenfeld and Rothstein, {Jeffrey D.} and Ericka Simpson and Nina Tolkoff-Rubin and Lorne Zinman and Shefner, {Jeremy M.} and S. Kalra and L. Korngut and H. Omar-Crawford and R. Sekhon and C. White and T. Benstead and I. Grant and S. Reidy and C. McIntosh and J. McKinley and C. Shoesmith and L. Zinman and S. Botez and Bouchard, {J. P.} and M. D'Amour and A. Genge and N. Hank and T. Levine and D. Saperstein and R. Alvarez and C. Banda and R. Garcia and M. Graves and H. Gruendler and J. Katz and F. Lin and C. Lomen-Hoerth and V. Martin and R. Miller and D. Moses and T. Mozaffar and L. Nist and B. Oskarsson and J. Rosenfeld and E. Tsimerinov and P. Tully and C. Villierme and K. Voelz and M. Wiedau-Pazos and Y. Rollins and K. Felice and E. Bayat and Kelly, {A. N.} and Boylan, {K. B.} and P. DeSaro and D. Koggan and A. Verma and J. Bordeau and J. Glass and M. Polak and B. Quarles and Rivner, {M. H.} and P. Casey and R. Sufit and C. Bodkin and S. Guingrich and J. Kincaid and A. Micheels and R. Pascuzzi and R. Snook and Barohn, {R. J.} and A. Dick and L. Herbelin and Dimachkie, {M. M.} and McVey, {A. L.} and M. Walsh and Y. Wang and J. Hutchison and E. Kasarskis and J. King and T. Tandy and S. Thomas and K. Vanderpool and J. Rothstein and P. Andres and M. Bellanich and Cudkowicz, {M. E.} and W. David and A. Goldenberg and Greenblatt, {D. J.} and L. Krivickas and L. Loci and M. Majkut and O. O'Connor and M. Parkinson and D. Pulley and J. Russell and L. Sullivan and H. Foley and D. Gelinas and Newman, {D. S.} and S. Bundlie and T. Leviton and S. Patel and C. Rohde and S. Swanson and E. Tiryaki and A. Fann and G. Hayat and A. Pestronk and Pattee, {G. L.} and B. Weber and M. Keroack and B. Belsh and J. Belsh and Mertz, {M. A.} and DeNero, {A. M.} and T. Imperato and Lange, {D. J.} and N. Kassebaum and D. MacGowan and H. Mitsumoto and Scelsa, {S. N.} and M. Shahbazi and Shefner, {J. M.} and L. Simionescu and Watson, {M. L.} and J. Wymer and E. Bravver and Brooks, {B. R.} and J. Caress and Cartwright, {M. S.} and T. Johnston-Crews and C. Lary and J. Shuh and A. Bartlett and N. Berry and Kissel, {J. T.} and R. Kuenzler and Pioro, {E. P.} and A. Quick and B. Ash and K. Goslin and A. Deboo and A. Giampole and T. Heiman-Patterson and D. Lacomis and L. McCluskey and M. Powell and S. Rana and L. Rojas and D. Rowlands and Z. Simmons and Stephens, {H. E.} and M. DeCandio and D. Stickler and Davis, {D. L.} and Donofrio, {P. D.} and S. Halton and S. Hand and M. Hastings and D. Heitzman and L. Lay and J. McCloskey and E. Simpson and M. Bromberg and A. Joshi and Phillips, {L. H.}",
year = "2014",
month = "11",
day = "1",
doi = "10.1016/S1474-4422(14)70222-4",
language = "English (US)",
volume = "13",
pages = "1083--1091",
journal = "The Lancet Neurology",
issn = "1474-4422",
publisher = "Lancet Publishing Group",
number = "11",

}

TY - JOUR

T1 - Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis

T2 - A multi-stage, randomised, double-blind, placebo-controlled trial

AU - Cudkowicz, Merit E.

AU - Titus, Sarah

AU - Kearney, Marianne

AU - Yu, Hong

AU - Sherman, Alexander

AU - Schoenfeld, David

AU - Hayden, Douglas

AU - Shui, Amy

AU - Brooks, Benjamin

AU - Conwit, Robin

AU - Felsenstein, Donna

AU - Greenblatt, David J.

AU - Keroack, Myles

AU - Kissel, John T.

AU - Miller, Robert

AU - Rosenfeld, Jeffrey

AU - Rothstein, Jeffrey D.

AU - Simpson, Ericka

AU - Tolkoff-Rubin, Nina

AU - Zinman, Lorne

AU - Shefner, Jeremy M.

AU - Kalra, S.

AU - Korngut, L.

AU - Omar-Crawford, H.

AU - Sekhon, R.

AU - White, C.

AU - Benstead, T.

AU - Grant, I.

AU - Reidy, S.

AU - McIntosh, C.

AU - McKinley, J.

AU - Shoesmith, C.

AU - Zinman, L.

AU - Botez, S.

AU - Bouchard, J. P.

AU - D'Amour, M.

AU - Genge, A.

AU - Hank, N.

AU - Levine, T.

AU - Saperstein, D.

AU - Alvarez, R.

AU - Banda, C.

AU - Garcia, R.

AU - Graves, M.

AU - Gruendler, H.

AU - Katz, J.

AU - Lin, F.

AU - Lomen-Hoerth, C.

AU - Martin, V.

AU - Miller, R.

AU - Moses, D.

AU - Mozaffar, T.

AU - Nist, L.

AU - Oskarsson, B.

AU - Rosenfeld, J.

AU - Tsimerinov, E.

AU - Tully, P.

AU - Villierme, C.

AU - Voelz, K.

AU - Wiedau-Pazos, M.

AU - Rollins, Y.

AU - Felice, K.

AU - Bayat, E.

AU - Kelly, A. N.

AU - Boylan, K. B.

AU - DeSaro, P.

AU - Koggan, D.

AU - Verma, A.

AU - Bordeau, J.

AU - Glass, J.

AU - Polak, M.

AU - Quarles, B.

AU - Rivner, M. H.

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AU - Goldenberg, A.

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AU - Majkut, M.

AU - O'Connor, O.

AU - Parkinson, M.

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AU - Lary, C.

AU - Shuh, J.

AU - Bartlett, A.

AU - Berry, N.

AU - Kissel, J. T.

AU - Kuenzler, R.

AU - Pioro, E. P.

AU - Quick, A.

AU - Ash, B.

AU - Goslin, K.

AU - Deboo, A.

AU - Giampole, A.

AU - Heiman-Patterson, T.

AU - Lacomis, D.

AU - McCluskey, L.

AU - Powell, M.

AU - Rana, S.

AU - Rojas, L.

AU - Rowlands, D.

AU - Simmons, Z.

AU - Stephens, H. E.

AU - DeCandio, M.

AU - Stickler, D.

AU - Davis, D. L.

AU - Donofrio, P. D.

AU - Halton, S.

AU - Hand, S.

AU - Hastings, M.

AU - Heitzman, D.

AU - Lay, L.

AU - McCloskey, J.

AU - Simpson, E.

AU - Bromberg, M.

AU - Joshi, A.

AU - Phillips, L. H.

PY - 2014/11/1

Y1 - 2014/11/1

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=84907978186&partnerID=8YFLogxK

U2 - 10.1016/S1474-4422(14)70222-4

DO - 10.1016/S1474-4422(14)70222-4

M3 - Article

C2 - 25297012

AN - SCOPUS:84907978186

VL - 13

SP - 1083

EP - 1091

JO - The Lancet Neurology

JF - The Lancet Neurology

SN - 1474-4422

IS - 11

ER -