A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy

Klopstock, Thomas; Yu‐Wai‐Man, Patrick; Dimitriadis, Konstantinos; Rouleau, Jacinthe; Heck, Suzette; Bailie, Maura; Atawan, Alaa; Chattopadhyay, Sandip; Schubert, Marion; Garip, Aylin; Kernt, Marcus; Petraki, D.; Rummey, Christian; Leinonen, Mika; Metz, Günther; Griffiths, Philip G.; Meier, Thomas; Chinnery, Patrick F.

doi:10.1093/brain/awr170

Cited by 468 publications

(359 citation statements)

References 23 publications

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“…Idebenone also has been evaluated in a controlled, international collaborative treatment trial of LHON [39]. LHON is associated with mutations in mtDNA affecting complex I of the ETC, is the most common mitochondrial disorder causing progressive blindness, and is most prevalent in young adult males.…”

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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Section: Idebenonementioning

confidence: 99%

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Kerr

2013

Neurotherapeutics

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“…This first randomized controlled trial in the mitochondrial disorder provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated. They investigated the treatment effect among patients with the 11778G>A and 3460G>A mutations [15]. Heitz et al described that in mice, idebenone penetrated into the eye at concentrations equivalent to those that protected retinal ganglion cells from complex I dysfunction in vitro.…”

Section: Discussionmentioning

confidence: 99%

Leber’s hereditary optic neuropathy - Case report

Iorga

Mihailovici

Costin

2018

rjo

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Leber's hereditary optic neuropathy is the most common mitochondrial condition and is characterized by bilateral, painless, subacute visual loss that develops during young adult life. LHON is a rare condition and this lack of knowledge can make doctors suspect and treat for other causes of vision loss. Typically, a series of tests are performed to confirm LHON diagnosis or exclude any other conditions. We presented the case of two brothers, HB, of 40 years old and HF, of 38 years old, who presented with a decrease in visual acuity in both eyes. The patients had been diagnosed with optic atrophy of unknown cause a long time ago, but no further investigations were made. They were treated with corticosteroids, antioxidants and vasodilators, but with no significant benefit. A blood test of the mitochondrial DNA, a magnetic resonance imaging and an optic coherence tomography of the optic nerve and macula were part of the following assessment of our patients. The mitochondrial DNA analyses revealed the 3460 G>A mutation on the mtND1 gene in both patients. Based on the medical history, the fundus aspect, the optic coherence tomography and the paraclinical investigations of the diagnosis of Leber's hereditary optic neuropathy were established in both patients. We started the treatment with idebenone and we evaluated the patients after three months. Keywords: Leber's hereditary optic neuropathy, mitochondrial DNA test, optic coherence tomography, idebenone Abbreviations: LHON = Leber's hereditary optic neuropathy, mtDNA = mitochondrial DNA, VA = visual acuity, CF = count fingers, OCT = optical coherence tomography, RNFL = retinal nerve fiber layer, GCL = ganglion cells layer, MS = multiple sclerosis, MRI = magnetic resonance imaging, MTI = magnetization transfer imaging, MTR = magnetization transfer ratio

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“…Three patients reported subjective improvement in visual acuity, one with monocular disease showed arrest of progression of visual loss to the other eye, and four demonstrated improvement in visual evoked potential. Klopstock et al 14 conducted a 24-week multicentre double-blind, randomised, placebo-controlled trial in 85 patients given idebenone at a dose of 900 mg/day. There was no significant difference in the overall group for best recovery of visual acuity.…”

Section: Discussionmentioning

confidence: 99%