Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved?

@article{Mitsumoto2014ClinicalTI,
  title={Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved?},
  author={Hiroshi Mitsumoto and Benjamin Rix Brooks and Vincenzo Silani},
  journal={The Lancet Neurology},
  year={2014},
  volume={13},
  pages={1127-1138}
}
Amyotrophic lateral sclerosis (ALS) is one of the most rapidly progressive neurodegenerative diseases of unknown cause. Riluzole is the only drug that slows disease progression. More than 50 randomised controlled trials (RCTs) of proposed disease-modifying drugs have failed to show positive results in the past half-century. In the past decade, at least 18 drugs have been tested in large phase 2 or 3 RCTs, including lithium, which was tested in several RCTs. Potential reasons for the negative… Expand
View on Elsevier
doi.org
192 Citations
Highly Influential Citations
7
Background Citations
52
Methods Citations
4

192 Citations

Citation Type

Citation Type

Advances in disease-modifying pharmacotherapies for the treatment of amyotrophic lateral sclerosis
TLDR
Post-hoc analyses reveal that future clinical trials should include disease-staging procedures, longer-term trials to correctly assess survival, genetic studies of participants to aid in stratification, and more similarity between the protocols on preclinical models and clinical trials. Expand
The clinical trial landscape in amyotrophic lateral sclerosis—Past, present, and future
TLDR
This work summarizes and classify interventional therapeutic strategies based on their molecular targets and phenotypic effects in ALS and discusses possible reasons for the failure of clinical trials in ALS. Expand
Innovating Clinical Trials for Amyotrophic Lateral Sclerosis
TLDR
A flexible design framework is proposed which naturally adapts the trial duration when inaccurate assumptions are made at the design stage such as the enrollment or survival rate and may serve a blueprint for future clinical trials in this population of patients. Expand
A retrospective review of the progress in amyotrophic lateral sclerosis drug discovery over the last decade and a look at the latest strategies
TLDR
A two-pronged approach may prove essential to achieve clinical efficacy in the identification of novel targets and preclinical testing in multiple models to identify biomarkers that can function in diagnostic, predictive and prognostic roles, and changes to clinical trial design and patient recruitment criteria are suggested. Expand
Shortcomings in the Current Amyotrophic Lateral Sclerosis Trials and Potential Solutions for Improvement
TLDR
This review has outlined the possible reasons for failure of ALS clinical trials, addressed the factors limiting timely diagnosis, and suggested possible solutions for future considerations for each of the shortcomings. Expand
Amyotrophic Lateral Sclerosis, 2016: existing therapies and the ongoing search for neuroprotection
TLDR
This article lays out the current understanding of disease genesis and physiology in relation to drug development in ALS, stressing important accomplishments and gaps in knowledge and discusses the prion-protein hypothesis of neurodegeneration. Expand
Stem cell treatments for amyotrophic lateral sclerosis: a critical overview of early phase trials
TLDR
This review covers the key advances from early phase clinical trials of stem cell therapy for ALS and identifies promising avenues and key challenges. Expand
Clinical trials in the ALS syndrome: it is time for change
  • M. Swash
  • Medicine
  • Journal of Neurology, Neurosurgery, and Psychiatry
  • 2019
Twenty-five years have passed since the first successful trial of riluzole in amyotrophic lateral sclerosis (ALS), a study that concluded that the drug had a modest effect in extending life… Expand
Edaravone in Amyotrophic Lateral Sclerosis’Lessons from the Clinical Development Program and the Importance of a Strategic Clinical Trial Design
TLDR
The edaravone clinical development program is discussed, the strategic clinical trial design is outlined, important lessons for future trials are highlighted, and future research incorporating relevant biomarkers are incorporated. Expand
Disease-modifying therapies in amyotrophic lateral sclerosis
TLDR
The pathological mechanisms relevant to ALS and current and future pharmacological and non-pharmacological trials, including gene and stem cells therapies, will be presented. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 103 REFERENCES
Emerging drugs for amyotrophic lateral sclerosis
TLDR
A review of recent discoveries relating to pathogenic mechanisms involved in disease development and progression in ALS highlights recent discoveries and their implications for the development of drug therapy. Expand
Of mice and men: Reconciling preclinical ALS mouse studies and human clinical trials
TLDR
Two separate studies provide an opportunity to reflect on how drugs for neurodegenerative disease are investigated and a new clinical trial of creatine was found to be ineffective in ALS, whereas a drug trial in an ALS mouse model finds for the first time that multiple drugs, three, additively slow down the disease. Expand
Current pharmacological management of amyotropic lateral sclerosis and a role for rational polypharmacy
TLDR
Based on the available data, it is the opinion that combination drug therapies should be considered for future clinical trials. Expand
Preventing familial amyotrophic lateral sclerosis: Is a clinical trial feasible?
TLDR
A clinical trial in fALS may be feasible although such a trial would likely require prolonged follow-up and would require a therapeutic agent with a large clinical effect in order to be adequately powered. Expand
A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group.
TLDR
The antiglutamate agent riluzole appears to slow the progression of amyotrophic lateral sclerosis, and it may improve survival in patients with disease of bulbar onset, according to a prospective, double-blind, placebo-controlled trial in 155 outpatients with Amyotrophicateral sclerosis. Expand
Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial
TLDR
The finding that minocycline has a harmful effect on patients with ALS has implications for trials of minocyCline in patients with other neurological disorders, and for how potential neuroprotective agents are screened for use in Patients with ALS. Expand
Can selection of rapidly progressing patients shorten clinical trials in amyotrophic lateral sclerosis?
TLDR
This strategy of selecting patients with rapidly progressing ALS for inclusion in exploratory, short phase II clinical trials offers substantial savings in costs and time, and could accelerate the process of testing potentially useful drugs for the treatment of ALS. Expand
Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis
TLDR
This study provided Class IV evidence that lithium carbonate does not slow the rate of decline of function in patients with ALS over 13 months, and the lack of therapeutic benefit and safety concerns, taken together with similar results from 2 other recent trials, weighs against the use of lithium Carbonate. Expand
Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials
  • V. Meininger, G. Bensimon, +6 authors W. Robberecht
  • Medicine
  • Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases
  • 2004
TLDR
Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS, and dose‐dependent side effects were largely associated with the serotonergic properties of the drug. Expand
Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial
TLDR
No evidence of benefit of lithium on survival in patients with ALS is found, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. Expand
...
1
2
3
4
5
...