Design and Initial Results of a Multi-Phase Randomized Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis

James D. Berry, Jeremy M. Shefner, Robin Conwit, David Schoenfeld, Myles Keroack, Donna Felsenstein, Lisa Krivickas, William S. David, Francine Vriesendorp, Alan Pestronk, James B. Caress, Jonathan Katz, Ericka Simpson, Jeffrey Rosenfeld, Robert Pascuzzi, Jonathan Glass, Kourosh Rezania, Jeffrey D. Rothstein, David J. Greenblatt, Merit E. Cudkowicz

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere61177
JournalPLoS One
Volume8
Issue number4
DOIs
StatePublished - Apr 17 2013

Fingerprint

ceftriaxone
Ceftriaxone
Amyotrophic Lateral Sclerosis
Pharmacokinetics
pharmacokinetics
Clinical Trials Data Monitoring Committees
Cerebrospinal fluid
cerebrospinal fluid
dosage
glutamates
Cerebrospinal Fluid
amyotrophic lateral sclerosis
Amino Acid Transport System X-AG
Safety
Ursodeoxycholic Acid
Monitoring
monitoring
placebos
transporters
Glutamic Acid

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Berry, J. D., Shefner, J. M., Conwit, R., Schoenfeld, D., Keroack, M., Felsenstein, D., ... Cudkowicz, M. E. (2013). Design and Initial Results of a Multi-Phase Randomized Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis. PLoS One, 8(4), [e61177]. https://doi.org/10.1371/journal.pone.0061177

Design and Initial Results of a Multi-Phase Randomized Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis. / Berry, James D.; Shefner, Jeremy M.; Conwit, Robin; Schoenfeld, David; Keroack, Myles; Felsenstein, Donna; Krivickas, Lisa; David, William S.; Vriesendorp, Francine; Pestronk, Alan; Caress, James B.; Katz, Jonathan; Simpson, Ericka; Rosenfeld, Jeffrey; Pascuzzi, Robert; Glass, Jonathan; Rezania, Kourosh; Rothstein, Jeffrey D.; Greenblatt, David J.; Cudkowicz, Merit E.

In: PLoS One, Vol. 8, No. 4, e61177, 17.04.2013.

Research output: Contribution to journalArticle

Berry, JD, Shefner, JM, Conwit, R, Schoenfeld, D, Keroack, M, Felsenstein, D, Krivickas, L, David, WS, Vriesendorp, F, Pestronk, A, Caress, JB, Katz, J, Simpson, E, Rosenfeld, J, Pascuzzi, R, Glass, J, Rezania, K, Rothstein, JD, Greenblatt, DJ & Cudkowicz, ME 2013, 'Design and Initial Results of a Multi-Phase Randomized Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis', PLoS One, vol. 8, no. 4, e61177. https://doi.org/10.1371/journal.pone.0061177
Berry JD, Shefner JM, Conwit R, Schoenfeld D, Keroack M, Felsenstein D et al. Design and Initial Results of a Multi-Phase Randomized Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis. PLoS One. 2013 Apr 17;8(4). e61177. https://doi.org/10.1371/journal.pone.0061177
Berry, James D. ; Shefner, Jeremy M. ; Conwit, Robin ; Schoenfeld, David ; Keroack, Myles ; Felsenstein, Donna ; Krivickas, Lisa ; David, William S. ; Vriesendorp, Francine ; Pestronk, Alan ; Caress, James B. ; Katz, Jonathan ; Simpson, Ericka ; Rosenfeld, Jeffrey ; Pascuzzi, Robert ; Glass, Jonathan ; Rezania, Kourosh ; Rothstein, Jeffrey D. ; Greenblatt, David J. ; Cudkowicz, Merit E. / Design and Initial Results of a Multi-Phase Randomized Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis. In: PLoS One. 2013 ; Vol. 8, No. 4.
@article{7a59274cb48e418f8bea60a5e8908f69,
title = "Design and Initial Results of a Multi-Phase Randomized Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis",
abstract = "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.",
author = "Berry, {James D.} and Shefner, {Jeremy M.} and Robin Conwit and David Schoenfeld and Myles Keroack and Donna Felsenstein and Lisa Krivickas and David, {William S.} and Francine Vriesendorp and Alan Pestronk and Caress, {James B.} and Jonathan Katz and Ericka Simpson and Jeffrey Rosenfeld and Robert Pascuzzi and Jonathan Glass and Kourosh Rezania and Rothstein, {Jeffrey D.} and Greenblatt, {David J.} and Cudkowicz, {Merit E.}",
year = "2013",
month = "4",
day = "17",
doi = "10.1371/journal.pone.0061177",
language = "English",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - Design and Initial Results of a Multi-Phase Randomized Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis

AU - Berry, James D.

AU - Shefner, Jeremy M.

AU - Conwit, Robin

AU - Schoenfeld, David

AU - Keroack, Myles

AU - Felsenstein, Donna

AU - Krivickas, Lisa

AU - David, William S.

AU - Vriesendorp, Francine

AU - Pestronk, Alan

AU - Caress, James B.

AU - Katz, Jonathan

AU - Simpson, Ericka

AU - Rosenfeld, Jeffrey

AU - Pascuzzi, Robert

AU - Glass, Jonathan

AU - Rezania, Kourosh

AU - Rothstein, Jeffrey D.

AU - Greenblatt, David J.

AU - Cudkowicz, Merit E.

PY - 2013/4/17

Y1 - 2013/4/17

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84876243023&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876243023&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0061177

DO - 10.1371/journal.pone.0061177

M3 - Article

C2 - 23613806

AN - SCOPUS:84876243023

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

M1 - e61177

ER -