Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis

Cudkowicz, Merit; Shefner, Jeremy M.; Simpson, Elizabeth; Grasso, Daniela; Yu, Hong; Zhang, Hui; Shui, Amy; Schoenfeld, David; Brown, Robert H.; Wieland, Scott; Barber, James David

doi:10.1002/mus.21059

Cited by 99 publications

(63 citation statements)

References 28 publications

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“…In this light, a number of compounds have been shown to induce HSP expression. Arimoclomol, an experimental drug that acts as an HSP coinducer, is in Phase II clinical trials for amyotrophic lateral sclerosis treatment (144,145). This drug has been shown to prolong the lifespan of the superoxide dismutase 1 (SOD1) enzyme in mice even when treatment was initiated after symptom onset (146,147).…”

Section: Therapeutic Potential Of Hspmentioning

confidence: 99%

Heat Shock Protein 70: Roles in Multiple Sclerosis

Mansilla

Montalbán

Espejo

2012

Mol Med

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Heat shock proteins (HSP) have long been considered intracellular chaperones that possess housekeeping and cytoprotective functions. Consequently, HSP overexpression was proposed as a potential therapy for neurodegenerative diseases characterized by the accumulation or aggregation of abnormal proteins. Recently, the discovery that cells release HSP with the capacity to trigger proinflammatory as well as immunoregulatory responses has focused attention on investigating the role of HSP in chronic inflammatory autoimmune diseases such as multiple sclerosis (MS). To date, the most relevant HSP is the inducible Hsp70, which exhibits both cytoprotectant and immunoregulatory functions. Several studies have presented contradictory evidence concerning the involvement of Hsp70 in MS or experimental autoimmune encephalomyelitis (EAE), the MS animal model. In this review, we dissect the functions of Hsp70 and discuss the controversial data concerning the role of Hsp70 in MS and EAE.

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Section: Therapeutic Potential Of Hspmentioning

confidence: 99%

Heat Shock Protein 70: Roles in Multiple Sclerosis

Mansilla

Montalbán

Espejo

2012

Mol Med

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“…Of the 27 trials, the data of 17 (63%) trials were donated, representing a mix of sources (industry, academic, and government-sponsored trials, including the Riluzole trials [13,14], lithium carbonate [15], creatine [16], celecoxib [17], topiramate [18], TCH-346 [19], brain-derived neurotrophic factor [20], ciliary neurotrophic factor [21], xaliproden [22], talampanel [23], arimoclomol [24], and gabapentin [25]). A full list of trials is available by referring to Attasi et al [26].…”

Section: Introductionmentioning

confidence: 99%

Being PRO-ACTive: What can a Clinical Trial Database Reveal About ALS?

et al. 2015

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Advancing research and clinical care, and conducting successful and cost-effective clinical trials requires characterizing a given patient population. To gather a sufficiently large cohort of patients in rare diseases such as amyotrophic lateral sclerosis (ALS), we developed the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) platform. The PRO-ACT database currently consists of >8600 ALS patient records from 17 completed clinical trials, and more trials are being incorporated. The database was launched in an open-access mode in December 2012; since then, >400 researchers from >40 countries have requested the data. This review gives an overview on the research enabled by this resource, through several examples of research already carried out with the goal of improving patient care and understanding the disease. These examples include predicting ALS progression, the simulation of future ALS clinical trials, the verification of previously proposed predictive features, the discovery of novel predictors of ALS progression and survival, the newly identified stratification of patients based on their disease progression profiles, and the development of tools for better clinical trial recruitment and monitoring. Results from these approaches clearly demonstrate the value of large datasets for developing a better understanding of ALS natural history, prognostic factors, patient stratification, and more. The increasing use by the community suggests that further analyses of the PRO-ACT database will continue to reveal more information about this disease that has for so long defied our understanding.

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“…Retention and protocol adherence data were collected on 601 participants enrolled in 5 ALS clinical trials conducted by the NEALS Consortium: 1) celebrex, 9 2) arimoclomol, 10 3) coenzyme Q10, 11 4) lithium, 6 and 5) KNS-760704 7 (table 1). Retention was defined as trial completion on study drug.…”

mentioning

confidence: 99%

Analysis of start-up, retention, and adherence in ALS clinical trials

Atassi¹,

Yerramilli-Rao²,

Szymonifka³

et al. 2013

Neurology

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Objective: To investigate predictors of trial start-up times, high attrition, and poor protocol adherence in amyotrophic lateral sclerosis (ALS) trials.Methods: Retrospective analysis of start-up times, retention, and protocol adherence was performed on 5 clinical studies conducted by the Northeast ALS Consortium and 50 ALS clinical trials identified by PubMed search. Predictors of start-up times were estimated by accelerated failure time models with random effects. Predictors of retention and protocol deviations were estimated by mixed-model logistic regression.Results: Median times for contract execution and institutional review board (IRB) approval were 105 days and 125 days, respectively. Contract execution was faster at sites with more ongoing trials (p 5 0.005), and more full-time (p 5 0.006) and experienced (p , 0.001) coordinators. IRB approval was faster at sites with more ongoing trials (p 5 0.010) and larger ALS clinics (p 5 0.038). Site activation after IRB approval was faster at sites with more full-time (p 5 0.038) and experienced (p , 0.001) coordinators. Twenty-two percent of surviving participants withdrew before completing the trial. Better participant functional score at baseline was an independent predictor of trial completion (odds ratio 1.29, p 5 0.002) and fewer protocol deviations (odds ratio 0.86, p 5 0.030).Conclusion: Delays in IRB review contribute the most to prolonged trial start-up times, and these timelines are faster in sites with more experienced staff. Strategies to improve protocol adherence and participants' retention may include enrolling people at early disease stages. The translation of basic research to clinical practice depends on the conduct of well-designed and efficient clinical trials. Delays in study start-up, high participant attrition, and poor adherence to the study protocol reduce trial validity and inflate the timelines and costs of drug development. In published clinical trials, enrollment and retention data are routinely reported; however, factors affecting study start-up times, retention, and adherence to the protocol are rarely mentioned. 1,2Conducting efficient clinical trials involves completing study start-up processes in a timely manner. This includes execution of the site contracts, obtaining institutional review board (IRB) approvals, and completing protocol, pharmacy, and outcomes trainings. Delays in the study start-up process can extend trial duration and costs, threaten trial feasibility, and delay answering important clinical questions.The internal validity of a clinical trial depends largely on good conduct including retention and maintaining good protocol adherence (i.e., complying with the study protocol). In addition, high attrition requires larger sample sizes to maintain statistical power and subsequently inflates trial duration and costs. 3,4 Amyotrophic lateral sclerosis (ALS) is a rare neurologic disorder that has many potential therapies currently in development.5 With a small patient population and limited funds, it is critical

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Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis

Cited by 99 publications

References 28 publications

Heat Shock Protein 70: Roles in Multiple Sclerosis

Heat Shock Protein 70: Roles in Multiple Sclerosis

Being PRO-ACTive: What can a Clinical Trial Database Reveal About ALS?

Analysis of start-up, retention, and adherence in ALS clinical trials

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