Efficacy and Safety of Leriglitazone in Patients With Friedreich Ataxia: A Phase 2 Double-Blind, Randomized Controlled Trial (FRAMES)

Abstract

Background and objectives: Friedreich ataxia (FRDA) is an autosomal recessive ataxia with no approved treatments. Leriglitazone is a selective peroxisome proliferator-activated receptor γ agonist that crosses the blood-brain barrier and, in preclinical models, improved mitochondrial function and energy production. We assessed effects of leriglitazone in patients with FRDA in a proof-of-concept study.

Methods: In this double-blind, randomized controlled trial, eligible participants (age 12-60 years) had genetically confirmed FRDA, a Scale for the Assessment and Rating of Ataxia (SARA) total score <25, and a SARA item 1 score of 2-6, inclusive. Key exclusion criteria were age at FRDA onset ≥25 years and history of cardiac dysfunction. Participants were randomly assigned (2:1) to receive a daily, oral, individualized dose of leriglitazone or placebo for 48 weeks. The primary endpoint was the change from baseline to week 48 in spinal cord area (C2-C3) (measured by MRI). Secondary endpoints included the change from baseline to week 48 in iron accumulation in the dentate nucleus (quantitative susceptibility mapping) and total N-acetylaspartate to myo-inositol (tNAA/mIns) ratio.

Results: Overall, 39 patients were enrolled (mean age 24 years; 43.6% women; mean time since symptom onset 10.5 years): 26 patients received leriglitazone (20 completed) and 13 received placebo (12 completed). There was no difference between groups in spinal cord area from baseline to week 48 (least-squares [LS] mean change [standard error (SE)]: leriglitazone, -0.39 [0.55] mm²; placebo, 0.08 [0.72] mm²; p = 0.61). Iron accumulation in the dentate nucleus was greater with placebo (LS mean change [SE]: leriglitazone, 0.10 [1.33] ppb; placebo, 4.86 [1.84] ppb; p = 0.05), and a numerical difference was seen in tNAA/mIns ratio (LS mean change [SE]: leriglitazone, 0.03 [0.02]; placebo, -0.02 [0.03]; p = 0.25). The most frequent adverse event was peripheral edema (leriglitazone 73.1%, placebo 0%).

Discussion: The primary endpoint of change in spinal cord area was not met. Secondary endpoints provide evidence supporting proof of concept for leriglitazone mode of action and, with acceptable safety data, support larger studies in patients with FRDA.

Trial registration information: ClinicalTrials.gov: NCT03917225; EudraCT: 2018-004405-64; submitted April 17, 2019; first patient enrolled April 2, 2019. clinicaltrials.gov/ct2/show/NCT03917225?term=NCT03917225&draw=2&rank=1.

Classification of evidence: This study provides Class I evidence that individualized dosing of leriglitazone, compared with placebo, is not associated with changes in spinal cord area in patients with FRDA.

Figure 1. CONSORT Diagram

The safety analysis set included all randomized patients who received at least 1 dose (partial or complete) of the study drug. The mITT analysis set included all patients who took at least 1 dose (partial or complete) of the study drug and had at least 1 postbaseline spinal cord area segment C2-C3 measurement and SARA assessment at the same visit. The PP analysis set included all patients in the mITT analysis set who did not have a major protocol deviation. CONSORT = Consolidated Standards of Reporting Trials; mITT = modified intent-to-treat; PP = per protocol; SARA = Scale for the Assessment and Rating of Ataxia.

Figure 2. Change From Baseline at Week 24 and Week 48 in Spinal Cord Cervical Area Cervical Segment C2-C3 (mm²), Estimated From MRI T1-Weighted Brain Images (mITT Population) (Primary Endpoint)

Data shown are mean ± SE. The LS mean (SE), 95% CI and p value for the difference between treatment arms, as assessed by ANCOVA (with treatment arm as a fixed effect and the baseline value as a covariate) are shown in the table. Baseline was defined as the last assessment performed before or on study day 1. N values in the table show the number of patients included in the ANCOVA analyses. ANCOVA = analysis of covariance; CI = confidence interval; LS = least-squares; mITT = modified intent-to-treat; SE = standard error.

Figure 3. Change From Baseline at Week 48 in (A) QSM Signal in the Dentate Nucleus (ppb), (B) Cervical Spinal Cord tNAA/mIns Ratio (as Assessed by MRS), (C) CCFS (Total Score), and (D) Patient Ranking for the CCFS, QSM, and MRS Endpoints, Showing Magnitude of Improvement or Worsening at Week 48 (mITT Population)

Data shown in A to C are mean ± SE, with the LS mean (SE), 95% CI and p value for the difference between treatment arms, as assessed by ANCOVA (with treatment arm as a fixed effect and the baseline as a covariate) shown in the tables. Baseline was defined as the last assessment performed before or on study day 1. n values show the number of patients included in the ANCOVA analyses. Dotted lines in panels (A–C) show the expected changes from baseline per year from the literature (panel A; panel B; panel C). Panel D shows ranking only for those patients who did not require imputation for the O'Brien composite sum of ranks test. ^aCCFS total score = log₁₀ (7 + Z pegboard dominant hand/10 + 4 *Z click dominant hand/10). ANCOVA = analysis of covariance; CCFS = cerebellar composite functional scale; CI = confidence interval; LS = least-squares; mITT = modified intent-to-treat; MRS = magnetic resonance spectroscopy; QSM = quantitative susceptibility mapping; SE = standard error; tNAA/mIns = total N-acetylaspartate concentration/myo-inositol.