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

Abstract

Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.

Figure 1

(A) Visual acuity efficacy end-points (filled arrows) between baseline and Week 24. (1) Primary end-point—best recovery/least worsening in visual acuity, one value per patient. (2) Main secondary end-point—change in best visual acuity, one value per patient. (3) Pre-specified secondary end-point—change in visual acuity of best eye at baseline, one value per patient. (4) Pre-specified secondary end-point—change in visual acuity of all eyes (both eyes of a patient considered independent), two values per patient. (B) Visual acuity at baseline for all patients. Both eyes are shown for each subject, connected by a solid line (grey squares = eye with better visual acuity; black squares = eye with worse visual acuity). BL = baseline; CF = finger counting; HM = hand motion; LP = light perception; VA = visual acuity.

Figure 2

Change in visual acuity (logMAR) end-points over time for the change in best recovery of visual acuity (A and B), change in best visual acuity (C and D), change in visual acuity of the patients’ best eye at baseline (E and F) and change in visual acuity for all eyes (G and H). For each analysis two populations are presented: the whole study population (n = 82, intent-to-treat population for visual acuity end-points) (A, C, E and G) and subpopulation of patients with discordant visual acuities at baseline (n = 30, B, D, F and H). Filled squares/solid line = idebenone group; filled circles/dashed lines = placebo group, P-values for comparison between idebenone and placebo groups. Data are estimated means (±SEM) from mixed model for repeat measures based on the change from baseline. ITT = intent-to-treat; VA = visual acuity; W = weeks.

Figure 3

Change in colour contrast sensitivity for red–green (Protan; A) and blue–yellow (Tritan; B). Data are estimated mean changes from baseline (± SEM) from mixed model for repeat measures. Filled squares/solid lines = idebenone group; filled circles/dashed lines = placebo group.

Figure 4

Retinal nerve fibre layer thickness at baseline for patients with disease onset of ≤6, 6–12 and >12 months (A). The mean retinal nerve fibre layer thickness for the temporal, superior, nasal and inferior retinal quadrants are shown. Relative change from baseline to Weeks 4, 12 and 24 in retinal nerve fibre layer thickness (B). n = 6/4 (idebenone/placebo) for eyes with disease onset of ≤6 months; n = 8/6 for eyes with disease onset of 6–12 months; n = 32/26 for eyes with disease onset of >12 months. Filled squares/solid line = idebenone group; filled circles/dashed line = placebo group. RNFLT = retinal nerve fibre layer thickness.