Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study

“…Deficiency of frataxin results in intramitochondrial iron accumulation and progressive neurological degeneration, cardiomyopathy, and diabetes. Over the last 13 years there have been 13 clinical trials of idebenone in FA, using progressively larger does and emerging to phase III trials, indicating that higher doses of idebenone are well tolerated and may stabilize neurological function in young patients with FA [35][36][37]. Again, these successive trials are instructive for smaller trials in less common mitochondrial disorders in that they involve multicenter collaboration, carefully controlled trial design, agreed upon primary outcomes, and build upon the experience of previous trials [3].…”

Section: Idebenonementioning

confidence: 99%

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Kerr

2013

Neurotherapeutics

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Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q 10 (CoQ 10 ; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ 10 ), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ 10 ), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, openlabel/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinicallyrelevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes.

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“…Idebenone may also shuttle electrons to the RC [38]. Unfortunately, in spite of several attempts at open and double-blind controlled trials, the efficacy of idebenone in Friedreich ataxia remains disputed [39]. Although there is indeed some evidence of a significant effect on a subset of patients with Friedreich ataxia [40], the limited cohorts of available patients compromise the power of these studies, and additional trials may be needed to achieve statistical significance.…”

Section: Targeting the Cellular Consequencesmentioning

confidence: 99%

Therapies in inborn errors of oxidative metabolism

Schiff¹,

Bénit²,

Jacobs³

et al. 2012

Trends in Endocrinology & Metabolism

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Mitochondrial diseases encompass a wide range of presentations and mechanisms, dictating a need to consider both broad-based and disease-specific therapies. The manifestations of mitochondrial dysfunction and the response to therapy vary between individuals. This probably reflects the genetic complexity of mitochondrial biology, which requires an excess of 2000 genes for proper function, with numerous interfering epigenetic and environmental factors. Accordingly, we are increasingly aware of the complexity of these diseases which involve far more than merely decreased ATP supply. Indeed, recent therapeutic progress has addressed only specific disease entities. In this review present and prospective therapeutic approaches will be discussed on the basis of targets and mechanism of action, but with a broad outlook on their potential applications.

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Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study

Cited by 86 publications

References 22 publications

Hereditary ataxias: overview

Hereditary ataxias: overview

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Therapies in inborn errors of oxidative metabolism

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