Title: Stratifying patients with Leber Hereditary Optic Neuropathy (LHON) for idebenone therapy using mitochondrial DNA analysis
Funder: Department of Health (England)

Abstract: Design: A parallel-arm double blind randomised placebo-controlled trial with stratification of patients with Leber hereditary optic neuropathy (LHON) based on molecular genetic testing for the m.11778G>A m.14484T>C and m.3460G>A mitochondrial DNA (mtDNA) mutations.Population: 114 subjects with a clinical diagnosis of LHON aged = 14 years with impaired visual acuity in at least one eye due to LHON Exclusion criteria will include pregnancy or breast-feeding excess alcohol or drug abuse.Interventions: 1) Stratification based on genetic testing: Molecular genetic testing of mitochondrial DNA (mtDNA) to identify patients harbouring the m.11778G>A m.3460G>A and m.14484T>C mutations. 2)Treatment: randomisation to 2250mg Raxone® (idebenone 150mg film-coated tablets) per day (divided into 3 equal daily doses with food) or placebo on a 1:1 basis for 48 weeks. Outcome measures: Primary outcome measure: proportion of patients presenting with clinically relevant recovery from visual acuity nadir. Secondary outcome measures: change in best visual acuity from baseline to week 48; best recovery in visual acuity (VA) from baseline to week 48; time to clinically relevant recovery (CRR) from the start of treatment; change in VA from baseline to week 48 for all eyes; change in best VA from nadir; best recovery in VA from nadir; best recovery in VA from nadir for all eyes; proportion of patients at week 48 without clinically relevant worsening from baseline; proportion of patients with VA <1.0 LogMAR at baseline and at 48 weeks; change in retinal nerve fibre layer thickness around the optic nerve and macula from baseline to week 48; CGIC (Clinical Global Impression of Change) from baseline to week 48; change in Health-Related Quality Of Life (HRQOL) assessed by the visual function (VF-14) index questionnaire from baseline to week 48.Assessment and follow-up: Safety will be assessed at screening baseline and weeks 4 12 24 36 48 and 52. A physical examination and measurement of vital signs will be done at every visit. Safety assessments will include: Heart rate (bpm); blood pressure (mmHg); respiratory rate (per minute); body weight (kg) Efficacy measures will be measured at baseline 12 24 36 and 48 weeks. Efficacy assessments will include: Visual acuity (best corrected LogMAR and clinically relevant response); Optic nerve fibre layer thickness measured as an overall average thickness; clinical global impression of change (CGI-C); Health-Related Quality of Life (HRQOL)Sample size: For the primary end point our power calculations are based on recent observations in the RHODOS trial. When considering the proportion of patients presenting with clinically relevant recovery from VA nadir we define this as an improvement in VA from off chart VA to on-chart by at least one full line on the ETDRS chart or by at least 2 lines on-chart European Medicines Agency Workshop on Ophthalmology EMA/450332/2012 p7/39). Additionally we consider that a significant difference in this proportion between the intervention (Idebenone) and control groups would be an absolute 25% difference. This is clinically significant because it represents a >300% relative improvement in clinically significant response rate between idebenone treated and placebo groups.In a responder analysis conducted in the RHODOS ITT population 16/53 (30%) patients randomised to Raxone® presented with clinically relevant recovery versus 2/28 (7%) placebo-randomised patients. Despite RHODOS being of a shorter duration than this study this 7% placebo recovery rate represents the best available estimate also based on prospectively collected data from the Santhera expanded access programme. With these values and an implicit comparison rate of 32% derived from the 7% placebo rate and the 25% absolute difference 51 patients in each group are required for 90% power at the 5% significance level. Assuming a loss to follow-up rate of 10% we will recruit and randomise 114 patients. This will require screening 120 patients to account for 5% with mtDNA heteroplasmy.Statistical analysis: For the primary outcome data will be compared using a logistic regression approach. The logistic regression model will also adjust for the stratification variable (specific mtDNA mutation) and gender in addition to baseline VA. Model fit and the use of interaction terms will be explored in addition to other covariates such as demographic variables using a pre-specified model selection process. This will initially consider univariate models for each covariate with those reaching a threshold significance being considered further in multivariate models. In order to obtain the final regression model covariates not reaching the threshold significance (other than potentially study arm specific mutation and gender) will be removed and the model refit. A significance level of 0.05 will be used throughout. Additionally more basic exploratory analyses (e.g. via the use of the chi-squared test) will also be performed. For the secondary outcomes the analysis strategy will be broadly similar to that described for the primary analysis. However as we consider some continuous outcome measures or measures which can be treated as such Analysis of Covariance methods will be used in place of logistic regression for these outcomes. The covariates identified to be of interest during the modelling process described for the primary outcome will be adjusted for in addition to study arm specific mutation and gender. Allowance will be made for the non-independence of outcomes within individual patients when considering any all eyes analyses. As the baseline value for the measures form part of the derivation of the change this will not be adjusted for explicitly in the modelling process. The secondary outcomes to be analysed in this fashion are: Change in best VA from baseline to week 48; Change in VA from baseline to week 48 for all eyes; Change in best VA from nadir; Best recovery in VA from baseline to week 48; Best recovery in VA from nadir; Best recovery in VA from nadir for all eyes; Time to clinically relevant recovery (CRR) from the start of treatment; Proportion of patients at week 48 without clinically relevant worsening from baseline. Clinically relevant worsening (CRW) from baseline is defined as a regression in VA of the equivalent of at least one full line on the ETDRS chart to off chart VA or the equivalent of at least 2 lines on-chart; Proportion of patients with VA<1.0 LogMAR both at baseline and 48 weeks; Change in retinal nerve fibre layer thickness around the optic nerve and macula from baseline to week 48; CGIC (Clinical Global Impression of Change) from baseline to week 48; Change in Health-Related Quality of Life (HRQOL) assessed by the visual function (VF-14) index questionnaire from baseline to week 48. A significance level of 0.05 will be used throughout. Once again more basic exploratory analyses (e.g. via the use of the t-test) will also be performed. Analysis groups: The primary analysis will be carried out between trial arms on an intention-to-treat basis. Should non-compliance to randomised intervention be found to be a problem a per-protocol analysis using an active treatment group defined by compliance to Idebenone will be performed using the same methodology. An analysis on participants in the Idebenone arm will also be performed on the outcome measures stated previously using groups defined by the specific mutation present (m.11778G>A m14484T>C and m3460G>A). Again a broadly similar methodology will be applied. Should a significant global difference be found between the three groups post-hoc pairwise comparisons will be performed to investigate this difference.Other exploratory analyses (such as on sub-groups defined by disease duration and the presence of asymmetric VA) may also be considered. A subgroup analyses of visual outcomes will be performed in patients with: (a) asymmetric visual acuities of greater than 0.2 LogMAR between the two affected eyes at baseline (b) average retinal nerve fibre layer thickness on OCT not more than 1 standard deviation below normal and (c) previous treatment with co-enzyme Q10 prior to trial enrolment. Further subgroup analyses to be considered are those defined by: (a) age group [<30 years and =30 years] (c) smoking status [current smokers and non-smokers] (d) visual acuity at VA nadir [with both eyes on-chart with at least one eye on-chart with both eyes off-chart] (e) visual acuity at baseline [with both eyes on-chart with at least one eye on-chart with both eyes off-chart] and (f) disease duration [as determined by the time elapsed since the first onset of visual loss]. Basic demographic data will also be tabulated by group at baseline.Timetables and recruitment: The total duration of recruitment is estimated to be 24 months. Patients with LHON will be assessed at one centre – the Royal Victoria Infirmary Newcastle-upon-Tyne Hospitals NHS Foundation Trust (NUTHFT). This site currently monitors over 250 patients with LHON which will form the primary recruitment base. NUTHFT will also recruit from a population of >2000 patients within the UK with LHON accessed through: (i) Patient support groups; (ii) Three Comprehensive Local Research Networks Clinical Specialty Groups (Nervous System Disorders Ophthalmology Genetics); (iii) The Association of British Neurologists Neuro-ophthalmology group; (iv) the British Isles Neuro-Ophthalmology Club (BINOC) and (v) Participant Identification Centres (PICs).


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL