Goldstein, A;
Rahman, S;
(2020)
Seeking impact: global perspectives on outcome measure selection for translational and clinical research for primary mitochondrial disorders.
Journal of Inherited Metabolic Disease
10.1002/jimd.12320.
(In press).
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Abstract
Primary mitochondrial disorders (PMDs) are challenging due to overall poor outcomes, no proven treatments, and a history of failed clinical trials, leading to a critical need to design future trials that can prove efficacy of an intervention. Selection of outcome measures for PMDs is complicated by extreme clinical, biochemical and genetic heterogeneity; PMDs are effectively a collection of nearly 400 individually ultra‐rare diseases. In clinical trials, outcome measures aim to evaluate, and ideally quantitate, the efficacy of an intervention in ameliorating clinical phenotype(s). The heterogeneity and multi‐systemic nature of PMDs makes it unlikely that a universal outcome measure will be applicable to all PMDs. Instead, a composite score of the individual’s most worrisome symptoms may be a preferable endpoint. A further challenge arises from the tension between finding outcomes suitable for use in clinical trials (able to produce a measurable change in a relatively short period of time, namely the duration of a clinical trial) versus measures that are clinically meaningful to individual patients. A number of clinical rating scales and proposed biomarkers have emerged to capture the features of PMDs for natural history and interventional trials. Here we review our collective experiences with clinical rating scales, patient‐reported outcome measures, and physiological, imaging, biochemical and muscle phenotypes as outcome measures in paediatric and adult PMDs in natural history studies and recent clinical trials. There is a pressing need to agree on a set of validated, robust, clinically meaningful outcome measures internationally, to facilitate the multicentre international clinical trials needed for optimal evaluation of novel therapies for these ultra‐rare diseases.
| Type: | Article |
|---|---|
| Title: | Seeking impact: global perspectives on outcome measure selection for translational and clinical research for primary mitochondrial disorders |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/jimd.12320 |
| Publisher version: | https://doi.org/10.1002/jimd.12320 |
| Language: | English |
| Additional information: | © 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
| Keywords: | Primary mitochondrial disorders (PMDs); outcome measures; biomarkers; clinical trials; common data elements; metabolic disorders; oxidative phosphorylation; primary endpoints |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10112265 |
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