Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis

Babu, Suma; Macklin, Eric A.; Jackson, Katherine M.; Simpson, Elizabeth; Mahoney, Katy; Yu, Hong; Walker, Jason; Simmons, Zachary; David, William S.; Barkhaus, Paul E.; Simionescu, Laura; Dimachkie, Mazen M.; Pestronk, Alan; Salameh, Johnny; Weiss, Michael D.; Brooks, Benjamin Rix; Schoenfeld, David; Shefner, Jeremy M.; Aggarwal, S.; Cudkowicz, Merit; Atassi, Nazem

doi:10.1080/21678421.2019.1672750

Cited by 13 publications

(4 citation statements)

References 33 publications

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“…In a small randomized controlled trial, tamoxifen was found to slow progression of ALS in a modest fashion 159 . A comparison of 40‐ and 80‐mg daily doses of tamoxifen with 30 mg a day of creatine in a unique selective‐design Phase 2 study showed superiority of the higher dose of tamoxifen compared to the lower dose and creatine, suggesting that high‐dose tamoxifen should be compared to placebo in a future study 160 . Other compounds currently being developed and in clinical trial with abundant preclinical evidence in several ALS models of autophagy include rapamycin (NCT03359538) and colchicine (NCT03693781) 161–169 …”

Section: Targeted Pathways In Als Pathogenesismentioning

confidence: 99%

Therapeutic targeting ofALSpathways: Refocusing an incomplete picture

Maragakis,

de Carvalho,

Weiss

2023

Ann Clin Transl Neurol

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Numerous potential amyotrophic lateral sclerosis (ALS)‐relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial. However, few successes have been observed with only modest effects. Along with an improved but incomplete understanding of ALS as a neurodegenerative disease is the evolution of more sophisticated and diverse in vitro and in vivo preclinical modeling platforms, as well as clinical trial designs. We highlight proposed pathological pathways that have been major therapeutic targets for investigational compounds. It is likely that the failures of so many of these therapeutic compounds may not have occurred because of lack of efficacy but rather because of a lack of preclinical modeling that would help define an appropriate disease pathway, as well as a failure to establish target engagement. These challenges are compounded by shortcomings in clinical trial design, including lack of biomarkers that could predict clinical success and studies that are underpowered. Although research investments have provided abundant insights into new ALS‐relevant pathways, most have not yet been developed more fully to result in clinical study. In this review, we detail some of the important, well‐established pathways, the therapeutics targeting them, and the subsequent clinical design. With an understanding of some of the shortcomings in translational efforts over the last three decades of ALS investigation, we propose that scientists and clinicians may choose to revisit some of these therapeutic pathways reviewed here with an eye toward improving preclinical modeling, biomarker development, and the investment in more sophisticated clinical trial designs.

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Section: Targeted Pathways In Als Pathogenesismentioning

confidence: 99%

Therapeutic targeting ofALSpathways: Refocusing an incomplete picture

Maragakis,

de Carvalho,

Weiss

2023

Ann Clin Transl Neurol

Self Cite

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show abstract

“…Initially, preclinical studies provided encouraging data as creatin was shown to delay the impairment of locomotor functions and extend lifespan [ 122 , 123 , 124 ]; however, a later study did not confirm these results [ 125 ]. Similarly, randomized controlled human trials evaluating the efficacy of creatine monohydrate, administered alone or in combination with other drugs (NCT00005766, NCT00005674, NCT00355576, NCT00070993, NCT00069186, NCT01257581) [ 126 , 127 , 128 ], showed that this compound did not improve disease progression or survival in ALS patients [ 129 ]. However, high CK levels have been correlated with a slower progression of the disease in ALS patients and mouse models [ 130 ], suggesting that providing supplements to the muscles could partially compensate for the catabolic effects of ALS hypermetabolism.…”

Section: Pharmacological and Nutritional Interventionsmentioning

confidence: 99%

Skeletal Muscle in ALS: An Unappreciated Therapeutic Opportunity?

Scaricamazza

Salvatori

Ferri

et al. 2021

Cells

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective degeneration of upper and lower motor neurons and by the progressive weakness and paralysis of voluntary muscles. Despite intense research efforts and numerous clinical trials, it is still an incurable disease. ALS had long been considered a pure motor neuron disease; however, recent studies have shown that motor neuron protection is not sufficient to prevent the course of the disease since the dismantlement of neuromuscular junctions occurs before motor neuron degeneration. Skeletal muscle alterations have been described in the early stages of the disease, and they seem to be mainly involved in the “dying back” phenomenon of motor neurons and metabolic dysfunctions. In recent years, skeletal muscles have been considered crucial not only for the etiology of ALS but also for its treatment. Here, we review clinical and preclinical studies that targeted skeletal muscles and discuss the different approaches, including pharmacological interventions, supplements or diets, genetic modifications, and training programs.

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“…The second trial (NCT01257581) was a "selection design" in which 60 PALS were randomly assigned to creatine 30g daily, tamoxifen 40mg daily, or tamoxifen 80mg daily (19). Outcomes including ALSFRS-R, SVC and muscle strength testing were assessed by a blinded observer over 38 weeks of follow up.…”

Section: Trialsmentioning

confidence: 99%

“…While no dose of tamoxifen is proven to slow ALS progression, the above-described selection trial suggested that 80 mg daily might be best for future trials (19). At this dose, tamoxifen would cost about $80 per month (22).…”

Section: Dosing Risk Costsmentioning

confidence: 99%

ALSUntangled 59: Tamoxifen

Bedlack

Kihuwa-Mani

Barkhaus

et al. 2021

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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Here we use the ALSUntangled methodology to review Tamoxifen as an ALS treatment. We show that it has plausible mechanisms, a positive preclinical study, a case report and 2 small trials suggesting benefits. We show that it appears reasonably safe, though there is a small risk of developing cancer with long term use. While we cannot yet endorse this as an ALS treatment, there is enough evidence to warrant another larger ALS trial.

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Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis

Cited by 13 publications

References 33 publications

Therapeutic targeting ofALSpathways: Refocusing an incomplete picture

Therapeutic targeting ofALSpathways: Refocusing an incomplete picture

Skeletal Muscle in ALS: An Unappreciated Therapeutic Opportunity?

ALSUntangled 59: Tamoxifen

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