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Randomized, double-blind, placebo-controlled study of interferon-? 1b in Friedreich Ataxia.

ABSTRACT: Objective:In vitro, in vivo, and open-label studies suggest that interferon gamma (IFN-? 1b) may improve clinical features in Friedreich Ataxia through an increase in frataxin levels. The present study evaluates the efficacy and safety of IFN-? 1b in the treatment of Friedreich Ataxia through a double-blind, multicenter, placebo-controlled trial. Methods:Ninety-two subjects with FRDA between 10 and 25 years of age were enrolled. Subjects received either IFN-? 1b or placebo for 6 months. The primary outcome measure was the modified Friedreich Ataxia Rating Scale (mFARS). Results:No difference was noted between the groups after 6 months of treatment in the mFARS or secondary outcome measures. No change was noted in buccal cell or whole blood frataxin levels. However, during an open-label extension period, subjects had a more stable course than expected based on natural history data. Conclusions:This study provides no direct evidence for a beneficial effect of IFN-?1b in FRDA. The modest stabilization compared to natural history data leaves open the possibility that longer studies may demonstrate benefit.

SUBMITTER: Lynch DR

PROVIDER: S-EPMC6414489 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Randomized, double-blind, placebo-controlled study of interferon-<i>γ</i> 1b in Friedreich Ataxia.

Lynch David R DR Hauser Lauren L McCormick Ashley A Wells McKenzie M Dong Yi Na YN McCormack Shana S Schadt Kim K Perlman Susan S Subramony Sub H SH Mathews Katherine D KD Brocht Alicia A Ball Julie J Perdok Renee R Grahn Amy A Vescio Tom T Sherman Jeffrey W JW Farmer Jennifer M JM

Annals of clinical and translational neurology 20190227 3

<h4>Objective</h4>In vitro, in vivo, and open-label studies suggest that interferon gamma (IFN-<i>γ</i> 1b) may improve clinical features in Friedreich Ataxia through an increase in frataxin levels. The present study evaluates the efficacy and safety of IFN-<i>γ</i> 1b in the treatment of Friedreich Ataxia through a double-blind, multicenter, placebo-controlled trial.<h4>Methods</h4>Ninety-two subjects with FRDA between 10 and 25 years of age were enrolled. Subjects received either IFN-<i>γ</i> ...[more]

PMID: 30911578

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Project description:IntroductionCurrently, no treatment that delays with the progression of Friedreich ataxia is available. In the majority of patients Friedreich ataxia is caused by homozygous pathological expansion of GAA repeats in the first intron of the FXN gene. Nicotinamide acts as a histone deacetylase inhibitor. Dose escalation studies have shown, that short term treatment with dosages of up to 4?g/day increase the expression of FXN mRNA and frataxin protein up to the levels of asymptomatic heterozygous gene carriers. The long-term effects and the effects on clinical endpoints, activities of daily living and quality of life are unknown.MethodsThe aim of the NICOFA study is to investigate the efficacy and safety of nicotinamide for the treatment of Friedreich ataxia over 24?months. An open-label dose adjustment wash-in period with nicotinamide (phase A: weeks 1-4) to the individually highest tolerated dose of 2-4?g nicotinamide/day will be followed by a 2 (nicotinamide group): 1 (placebo group) randomization (phase B: weeks 5-104). In the nicotinamide group, patients will continue with their individually highest tolerated dose between 2 and 4?g/d per os once daily and the placebo group patients will be receiving matching placebo. Safety assessments will consist of monitoring and recording of all adverse events and serious adverse events, regular monitoring of haematology, blood chemistry and urine values, regular measurement of vital signs and the performance of physical examinations including cardiological signs. The primary outcome is the change in the Scale for the Assessment and Rating of Ataxia (SARA) over time as compared with placebo in patients with Friedreich ataxia based on the linear mixed effect model (LMEM) model. Secondary endpoints are measures of quality of life, functional motor and cognitive measures, clinician's and patient's global impression-change scales as well as the up-regulation of the frataxin protein level, safety and survival/death.PerspectiveThe NICOFA study represents one of the first attempts to assess the clinical efficacy of an epigenetic therapeutic intervention for this disease and will provide evidence of possible disease modifying effects of nicotinamide treatment in patients with Friedreich ataxia.Trial registrationEudraCT-No.: 2017-002163-17, ClinicalTrials.gov NCT03761511.

Project description:Background and objectivesFriedreich 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.MethodsIn 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.ResultsOverall, 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%).DiscussionThe 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 informationClinicalTrials.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 evidenceThis 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.

Project description:Memantine, an uncompetitive N-methyl-d-aspartate receptor antagonist, is currently approved by the US Food and Drug Administration for the treatment of moderate to severe Alzheimer's disease. Anecdotal reports have suggested that memantine may improve neurologic and cognitive symptoms of individuals with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS); however, its efficacy and safety in this population have not been assessed in a controlled trial.Individuals with FXTAS aged 34-80 years were enrolled in a randomized, double-blind, placebo-controlled, 1-year trial between September 2007 and August 2012. Inclusion required definite, probable, or possible FXTAS in clinical stages 1-5 according to previously published criteria. Primary outcome measures were the Behavioral Dyscontrol Scale (BDS) score and CATSYS intention tremor severity.Ninety-four participants were randomized from 205 screened; of those, 43 and 45 started treatment with memantine (titrated to 10 mg twice daily) and placebo, respectively. Thirty-four participants receiving memantine and 36 receiving placebo completed the 1-year endpoint assessment (n = 70). Intention-to-treat analysis showed no improvement with respect to intention tremor severity (mean [SD] values with memantine vs placebo: 1.05 [0.73] vs 1.89 [2.19], P = .047) or BDS score (16.12 [5.43] vs 15.72 [3.93], P = .727) at follow-up. Post hoc analyses of participants with early FXTAS (stage ? 3), those with late FXTAS (stage > 3), and those in different age groups (? 65 years and > 65 years) also indicated no significant improvement. More frequent mild adverse events were observed in the placebo group, while more frequent moderate adverse events occurred in the memantine group (P = .007).This randomized, double-blind, placebo-controlled trial of memantine for individuals with FXTAS showed no benefit compared to placebo with respect to the selected outcome measures.ClinicalTrials.gov identifier: NCT00584948.

Dataset Information

Randomized, double-blind, placebo-controlled study of interferon-? 1b in Friedreich Ataxia.

Publications

Randomized, double-blind, placebo-controlled study of interferon-<i>γ</i> 1b in Friedreich Ataxia.

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