Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Abstract

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.

A View of the Therapy for Bell’s Palsy Based on Molecular Biological Analyses of Facial Muscles

“…In patients with SD having Bell's palsy, mitochondrial cytopathy may develop with ATP synthesis impairment. As this state is similar to that seen in various mitochondrial diseases, we consider that therapy with pyruvate and MA-5 could be effective [7,8] . We also propose neurovascular free muscle transfer as an effective surgery for patients with SD having Bell's palsy.…”

Meeting report from the Mitochondrial Medicine Southeast Regional Symposium — understanding mitochondrial disease and mitochondrial dysfunction: Opportunities and impacts in the clinic and laboratory

“…The reasons for the evolution were the recognition that the shotgun approach of using all the vitamins and cofactors does not always work, the availability of evolving clinical trial evidence showing that some therapies do not work at all, and the expense involved in taking many vitamins and cofactors [5].…”

Mitochondrial DNA-related disorders: emphasis on mechanisms and heterogeneity

“…For a detailed review of each of these molecules we refer to the very valuable work of others (Parikh et al, 2009;Kanabus et al, 2014). Compounds undergoing clinical trials between 1997 and 2012 were also recently reviewed (Kerr, 2013).…”