Can we eliminate placebo in ALS clinical trials?

Bryan, Wilson W.; Hoagland, Rebecca; Murphy, James R.; Armon, Carmel; Barohn, Richard J.; Goodpasture, Jessie C.; Miller, Robert G.; Parry, Gareth; Petajan, Jack H.; Ross, Mark A.; Stromatt, Scott; Belsh, Jerry M.; Buchman, Aron S.; Donofrio, Peter D.; Eisen, Andrew; Gan, Richard A.; Gutmann, Laurie; Horowitz, Steven H.; Jackon, Carlayne E.; Johnston, Wendy; Kelly, John J.; Mandler, Raúl N.; Massey, Janice M.; McGuire, Dawn; Newman, Daniel S.; Pascuzzi, Robert M.; Phillips, Lawrence H.; Rivner, Michael H.; Rubin, Mark A.; Russo, Louis; Sergay, Stephen M.; Sumner, Austin J.; Swenson, Michael R.; Teitel, Lawrence

doi:10.1080/14660820310006661

Cited by 16 publications

(12 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a prospective register-based study, the rates of progression of respiratory, lower limb and bulbar impairment during the first six months after diagnosis (measured with FVC, MRC scale and bulbar scale, respectively) were independent prognostic factors in the Cox multivariable model (25). Similar data were found from the analysis of two different series of patients enrolled in the placebo arm of two clinical trials (16,48). In a recent paper on a small series, the progression rate of ALSFRS-R score evaluated at presentation was significantly related to ALS prognosis (49).…”

Section: Methodological Considerationssupporting

confidence: 77%

Prognostic factors in ALS: A critical review

Chiò¹,

Logroscino

Hardiman

et al. 2009

Amyotrophic Lateral Sclerosis

894

537

View full text Add to dashboard Cite

We have performed a systematic review to summarize current knowledge concerning factors related to survival in ALS and to evaluate the implications of these data for clinical trials design. The median survival time from onset to death ranges from 20 to 48 months, but 10–20% of ALS patients have a survival longer than 10 years. Older age and bulbar onset are consistently reported to have a worse outcome. There are conflicting data on gender, diagnostic delay and El Escorial criteria. The rate of symptom progression was revealed to be an independent prognostic factor. Psychosocial factors, FTD, nutritional status, and respiratory function are also related to ALS outcome. The effect of enteral nutrition on survival is still unclear, while NIPPV has been found to improve survival. There are no well established biological markers of progression, although some are likely to emerge in the near future. These findings have relevant implications for the design of future trials. Randomization, besides the type of onset, should take into account age, respiratory status at entry, and a measure of disease progression pre-entry. Alternative trial designs can include the use of natural history controls, the so-called minimization method for treatment allocation, and the futility approach.

show abstract

Section: Methodological Considerationssupporting

confidence: 77%

Prognostic factors in ALS: A critical review

Chiò¹,

Logroscino

Hardiman

et al. 2009

Amyotrophic Lateral Sclerosis

894

537

View full text Add to dashboard Cite

show abstract

“…The basis of the analysis was the assumption that for muscles undergoing active denervation, EIM phase, like most other outcome measures, falls nearly linearly with time (Bryan et al, 2003), and thus the slope of each parameter over time can be calculated and compared. The structure of this planned hypothetical trial was as follows: 100 patients receiving drug, 100 patients receiving placebo, followed for one year with bi-monthly evaluations, with a one-sided 0.05 significance level, and a 2% per month dropout rate.…”

Section: Discussionmentioning

confidence: 99%

“…Many measures have been shown to decline over time in ALS, with some having quite linear characteristics (Bryan et al, 2003). However, slow rates of decline combined with variability of measurement makes small changes in disease status very difficult to detect.…”

Section: Introductionmentioning

confidence: 99%

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

Rutkove

Zhang

Schoenfeld

et al. 2007

Clinical Neurophysiology

View full text Add to dashboard Cite

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.

show abstract

“…Genome wide association studies (GWAS) in sporadic ALS should be intensified to allow genome-based subgroup analyses in trials (Dunckley et al, 2007; Schymick et al, 2007; Valdmanis et al, 2009). Finally, innovative trial designs that may allow to judge early on whether a drug likely has no efficacy (futility designs), or smaller trials against cleverly controlled database controls need to be further explored (Bryan et al, 2003; Moore and Miller, 2004; Palesch and Tilley, 2004; Shefner et al, 2004; Cheung et al, 2006; Czaplinski et al, 2006; Gordon et al, 2007a, 2008; Schoenfeld and Cudkowicz, 2008; Gordon, 2009; Simmons, 2009; Aggarwal et al, 2010). …”

Section: Lessons Learnedmentioning

confidence: 99%

Neurotrophic growth factors for the treatment of amyotrophic lateral sclerosis: where do we stand ?

2010

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive loss of motoneurons, motor weakness and death within 3–5 years after disease onset. Therapeutic options remain limited despite substantial number of approaches that have been tested clinically. Many neurotrophic growth factors are known to promote the survival of neurons and foster regeneration in the central nervous system. Various neurotrophic factors have been investigated pre-clinically and clinically for the treatment of ALS. Although pre-clinical data appeared promising, no neurotrophic factors succeeded yet in a clinical phase III trial. In this review we discuss the rationale behind those factors, possible reasons for clinical failures, and argue for a renewal of hope in this powerful class of drugs for the treatment of ALS.

show abstract

Can we eliminate placebo in ALS clinical trials?

Abstract: Natural history controls may be useful in ALS exploratory trials that use arm megascore slope as the primary outcome measure. However, there are distinct limitations to the use of natural history controls, so that Phase 3 ALS clinical trials require placebo controls.

Cited by 16 publications

References 6 publications

Prognostic factors in ALS: A critical review

Prognostic factors in ALS: A critical review

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

Neurotrophic growth factors for the treatment of amyotrophic lateral sclerosis: where do we stand ?

Contact Info

Product

Resources

About