Trial of celecoxib in amyotrophic lateral sclerosis

Cudkowicz, Merit; Shefner, Jeremy M.; Schoenfeld, David; Zhang, Hui; Andreasson, Katrin I.; Rothstein, Jeffrey D.; Drachman, Daniel B.

doi:10.1002/ana.20903

Cited by 273 publications

(173 citation statements)

References 36 publications

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“…Few genetic factors that modify ALS survival are reported (19,20,47); none were identified in the previous ALS genome analyses (21)(22)(23)(24)46). The identification of KIFAP3 as a determinant of progression rate of sporadic ALS is therefore promising; insights into this pathway may provide new targets for therapies to slow this devastating disease, for example, by reducing levels of KIFAP3 expression or modifying its interactions with 1 or more protein binding partners.…”

Section: Discussionmentioning

confidence: 99%

Reduced expression of the Kinesin-Associated Protein 3 ( KIFAP3 ) gene increases survival in sporadic amyotrophic lateral sclerosis

Landers

Melki

Meininger

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

165

109

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Amyotrophic lateral sclerosis is a degenerative disorder of motor neurons that typically develops in the 6th decade and is uniformly fatal, usually within 5 years. To identify genetic variants associated with susceptibility and phenotypes in sporadic ALS, we performed a genome-wide SNP analysis in sporadic ALS cases and controls. A total of 288,357 SNPs were screened in a set of 1,821 sporadic ALS cases and 2,258 controls from the U.S. and Europe. Survival analysis was performed using 1,014 deceased sporadic cases. Top results for susceptibility were further screened in an independent sample set of 538 ALS cases and 556 controls. SNP rs1541160 within the KIFAP3 gene (encoding a kinesin-associated protein) yielded a genomewide significant result (P ‫؍‬ 1.84 ؋ 10 ؊8 ) that withstood Bonferroni correction for association with survival. Homozygosity for the favorable allele (CC) conferred a 14.0 months survival advantage. Sequence, genotypic and functional analyses revealed that there is linkage disequilibrium between rs1541160 and SNP rs522444 within the KIFAP3 promoter and that the favorable alleles of rs1541160 and rs522444 correlate with reduced KIFAP3 expression. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. We have identified a variant within the KIFAP3 gene that is associated with decreased KIFAP3 expression and increased survival in sporadic ALS. These findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability.genome-wide association study ͉ single nucleotide polymorphism A myotrophic lateral sclerosis (ALS) is an age-dependent, degenerative disorder of motor neurons (1) that typically develops in the 6th decade and is uniformly fatal, usually within 5 years (2). Approximately 10% of ALS cases are dominantly inherited (3); 20% of these are caused by mutations in the gene encoding copper/zinc superoxide dismutase 1 (SOD1) (4); mutations in the TARDBP gene (5, 6) account for Ϸ5% of cases. Rare familial cases arise from mutations in genes encoding the vesicle-associated membrane associated protein B (7), alsin (a RAB5-guanine nucleotide exchange factor) (8, 9), senataxin (10) or dynactin (11). Recently, we reported that Ϸ5% of familial ALS cases are due to mutations in the FUS/TLS gene (12, 13) whose product binds DNA and RNA, as does TARDBP. The cause of sporadic ALS is thought to be multifactorial, with environmental, infectious and genetic etiologies. Reported associations with variants in diverse genes (14-25) have proven difficult to replicate. Advances in the technology for large-scale genotyping of single nucleotide polymorphisms (SNPs) have facilitated unbiased, genome-wide association studies. Examples include the identification of IL2RA and IL7RA variants as risk factors for multiple sclerosis (26-28) and the recent reports of 6 new gene regions associated with type 2 diabetes (29)(30)(31)(32)(33)(34)(35). To test the hypothesis that commonly occurring genetic

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Section: Discussionmentioning

confidence: 99%

Reduced expression of the Kinesin-Associated Protein 3 ( KIFAP3 ) gene increases survival in sporadic amyotrophic lateral sclerosis

Landers

Melki

Meininger

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

165

109

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“…The potential power was calculated, assuming the treatment effect was 30%, 20% and 10% based on the slopes of the EIM megascore and global MMT. The data obtained here were also compared to the ALSFRS-R and MVICT arm strength megascore data obtained from a previous trial of celecoxib in ALS (Cudkowicz et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Note that the ALSFRS-R and MVICT megascore values virtually overlie one another. *Data derived from celecoxib in ALS study (Cudkowicz et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…While recent trials have failed to demonstrate benefit of a variety of therapeutic interventions, including celecoxib, topiramate, creatine (Cudkowicz et al, 2003;Shefner et al, 2004;Cudkowicz et al, 2006), advances in basic science are leading to a proliferation of new agents that will require clinical evaluation. A significant problem in clinical trial design is that large numbers of patients must be studied for long time periods for modest therapeutic benefit to be appreciated, making the design of phase II proof-of-concept trials challenging.…”

Section: Introductionmentioning

confidence: 99%

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Electrical impedance myography to assess outcome in amyotrophic lateral sclerosis clinical trials

Rutkove

Zhang

Schoenfeld

et al. 2007

Clinical Neurophysiology

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Objective-Standard outcome measures used for amyotrophic lateral sclerosis (ALS) clinical trials, including the ALS Functional Rating Scale-revised (ALSFRS-R), maximal voluntary isometric contraction testing (MVICT), and manual muscle testing (MMT) are limited in their ability to detect subtle disease progression. Electrical impedance myography (EIM) is a new non-invasive technique that provides quantitative data on muscle health by measuring localized tissue impedance. This study investigates whether EIM could provide a new outcome measure for use in ALS clinical trials work.Methods-Fifteen ALS patients underwent repeated EIM measurements of one or more muscles over a period of up to 18 months and the primary outcome variable, θ z-max , measured. The θ z-max megascore was then calculated using the same approach as has been applied in the past for MVICT. This and the MMT data were then used to assess each measure's statistical power to detect a given effect on disease progression in a hypothetical planned clinical therapeutic trial.Results-θ z-max showed a mean decline of about 21% for the test period, averaged across all patients and all tested muscles. The θ z-max megascore had a power of 73% to detect a 10% treatment effect in our planned hypothetical trial, as compared to a 28% power for MMT. These results also compared favorably to historical data for ALSFRS-R and MVICT arm megascore from the trial of celecoxib in ALS, where both measures had only a 23% power to detect the same 10% treatment effect.Conclusions-The θ z-max megascore may provide a powerful new outcome measure for ALS clinical trials.Significance-The application of EIM to future ALS trials may allow for smaller, faster studies with an improved ability to detect subtle treatment effects.

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“…In a trial of celecoxib in ALS [23], no significant differences between celecoxib and placebo were found, including for muscle strength. As previously noted, leg strength declined slightly slower than arm strength.…”

Section: Quantitative Muscle Testingmentioning

confidence: 93%

Strength Testing in Motor Neuron Diseases

Shefner

2017

Neurotherapeutics

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Loss of muscle strength is a cardinal feature of all motor neuron diseases. Functional loss over time, including respiratory dysfunction, inability to ambulate, loss of ability to perform activities of daily living, and others are due, in large part, to decline in strength. Thus, the accurate measurement of limb muscle strength is essential in therapeutic trials to best understand the impact of therapy on vital function. While qualitative strength measurements show declines over time, the lack of reproducibility and linearity of measurement make qualitative techniques inadequate. A variety of quantitative measures have been developed; all have both positive attributes and limitations. However, with careful training and reliability testing, quantitative measures have proven to be reliable and sensitive indicators of both disease progression and the impact of experimental therapy. Quantitative strength measurements have demonstrated potentially important therapeutic effects in both amyotrophic lateral sclerosis and spinobulbar muscular atrophy, and have been shown feasible in children with spinal muscular atrophy. The spectrum of both qualitative and quantitative strength measurements are reviewed and their utility examined in this review.

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Trial of celecoxib in amyotrophic lateral sclerosis

Abstract: At the dosage studied, celecoxib did not have a beneficial effect on research subjects with ALS, and it was safe. A biological effect of celecoxib was not demonstrated in the cerebrospinal fluid. Further studies of celecoxib at a dosage of 800 mg/day in ALS are not warranted.

Cited by 273 publications

References 36 publications

Reduced expression of the Kinesin-Associated Protein 3 ( KIFAP3 ) gene increases survival in sporadic amyotrophic lateral sclerosis

Reduced expression of the Kinesin-Associated Protein 3 ( KIFAP3 ) gene increases survival in sporadic amyotrophic lateral sclerosis

Electrical impedance myography to assess outcome in amyotrophic lateral sclerosis clinical trials

Strength Testing in Motor Neuron Diseases

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