Lipoic acid in secondary progressive MS

Objective: To determine whether lipoic acid (LA), an endogenously produced antioxidant, slowed the whole-brain atrophy rate and was safe in secondary progressive MS (SPMS). Methods: Patients with SPMS aged 40–70 years enrolled in a single center, 2-year, double-blind, randomized trial of daily oral 1,200mg LA vs placebo. Primary outcomewas change in annualized percent change brain volume (PCBV). Secondary outcomes were changes in rates of atrophy of segmented brain, spinal cord, and retinal substructures, disability, quality of life, and safety. Intention-to-treat analysis used linear mixed models. Results: Participation occurred between May 2, 2011, and August 14, 2015. Study arms of LA (n5 27) and placebo (n5 24) were matched with mean age of 58.5 (SD 5.9) years, 61%women, mean disease duration of 29.6 (SD 9.5) years, and median Expanded Disability Status Score of 6.0 (interquartile range 1.75). After 2 years, the annualized PCBV was significantly less in the LA arm compared with placebo (20.21 [standard error of the coefficient estimate (SEE) 0.14] vs 20.65 [SEE 0.10], 95% confidence interval [CI] 0.157–0.727, p5 0.002). Improved Timed 25Foot Walk was almost but not significantly better in the LA than in the control group (20.535 [SEE 0.358] vs 0.137 [SEE 0.247], 95% CI 21.37 to 0.03, p 5 0.06). Significantly more gastrointestinal upset and fewer falls occurred in LA patients. Unexpected renal failure (n 5 1) and glomerulonephritis (n 5 1) occurred in the LA cohort. Compliance, measured by pill counts, was 87%. Conclusions: LA demonstrated a 68% reduction in annualized PCBV and suggested a clinical benefit in SPMS while maintaining favorable safety, tolerability, and compliance over 2 years. ClinicalTrials.gov identifier: NCT01188811. Classification of evidence: This study provides Class I evidence that for patients with SPMS, LA reduces the rate of brain atrophy. Neurol Neuroimmunol Neuroinflamm 2017;4:e374; doi: 10.1212/ NXI.0000000000000374 GLOSSARY AE 5 adverse event; CI 5 confidence interval; EAE 5 experimental autoimmune encephalomyelitis; EDSS 5 Expanded Disability Status Scale; GI5 gastrointestinal; ITT5 intention to treat; LA5 lipoic acid;MP-RAGE5magnetization-prepared rapid acquisition gradient echo; OCT 5 optical coherence tomography; PCBV 5 percent change brain volume; PI 5 principal investigator; RRMS 5 relapsing-remitting MS; SAE 5 serious AE; SEE 5 standard errors of the coefficient estimate; SPMS 5 secondary progressive MS. By 2 decades, the majority with relapsing-remitting MS (RRMS) have secondary progressive MS (SPMS). SPMS pathophysiology likely involves mitochondrial dysfunction, microglial activation, vascular endothelial disruption, and effects of meningeal lymphoid-like tissues. The resulting neurodegeneration and accelerated brain atrophy correlate with functional disability; thus whole-brain atrophy is the current gold-standard MRI surrogate outcome measure for From the Neurology Division (R.S., V.Y., M.C., E.K., D.B.), Research Service (K.P., E.H.), and Department of Ophthalmology (K.W.), Veterans Affairs Portland Health Care System, OR; and Department of Neurology (R.S., C.M., K.W., V.Y., E.K., F.H., J.S., D.B.), Advanced Imaging Research Center (K.P.), and Casey Eye Institute (K.W.), Oregon Health & Science University, Portland. Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was funded by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Neurology.org/nn Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 SPMS trials. Targeting specific pathophysiologic processes is a rational strategy for treating SPMS. Lipoic acid (LA) is an endogenously produced antioxidant with multiple biological functions including free-radical scavenging, metallic ion chelation, regeneration of intracellular glutathione, and oxidative damage repair of macromolecules. In mitochondria, the LA/dihydrolipoic acid redox couple is a key cofactor for the pyruvate dehydrogenase complex of oxidative respiration and aids nucleic acid synthesis. LA modulates the PKB/ Akt signaling pathway important for vascular endothelial integrity, affects transcription factor Nrf2, and acts as an insulin mimetic. Our center and others have shown that LA reduced disability in experimental autoimmune encephalomyelitis (EAE), diminished inflammatory cell migration into spinal cords and optic nerves, and inhibited macrophage/ microglial activation. Oral ingestion of LA by patients with MS produced blood levels comparable with those in EAE. In clinical trials, LA is well tolerated; common adverse reactions were gastrointestinal (GI) intolerance, headache, malodorous urine, and rash. Herein, we report results of a 2year, randomized controlled trial to determine whether LA reduced rates of whole-brain atrophy, slowed clinical deterioration, and was safe in SPMS. METHODS Study design. This was a prospective, single-site, 2-year, phase II, double-blind, randomized, placebo-controlled trial of 1,200 mg daily oral racemic LA to answer the following primary research question with Class I level of evidence: would LA reduce the rate of whole-brain atrophy in SPMS? Secondary research questions were to determine whether LA would reduce rates of atrophy of segmented brain, spinal cord, and retinal substructures, reduce deterioration of disability and quality of life, and be safe in SPMS. Recruitment occurred between May 2011 and October 2013, with last visit being in August 2015. The study was conducted at the Veterans Affairs Portland Health Care System (VAPORHCS), Portland, OR, with some procedures at Oregon Health & Science University (OHSU), Portland, OR. Participants. Inclusion criteria were ages 40–70 years, prior RRMS (2005 McDonald criteria), and current SPMS defined by MS disability progression in the absence of clinical relapse during the prior 5 years as determined by the principal investigator (PI) based on history and chart review. Progression was defined as sufficient to change a Functional System on the Expanded Disability Status Scale (EDSS) or effect a meaningful functional change (e.g., stopped working due to cognitive decline). Participants were permitted to start, stop, or continue glatiramer acetate or b-interferon during the study. Exclusion criteria were use of natalizumab, immunosuppressants, chemotherapies, or scheduled IV corticosteroid treatments within 1 year of enrollment, corticosteroid treatment for relapse within 60 days of enrollment, LA within 30 days of enrollment, MRI constraints, self-reported ocular disease that could confound optical coherence tomography (OCT) interpretation, pregnant or breastfeeding, significant active concurrent illness, uncontrolled or insulindependent diabetes, and lack of English fluency. Because of slow recruitment during the first 8 months, the EDSS limit of 6.0 was eliminated. Standard protocol approvals, registrations, and patient consents. The study was approved by VAPORHCS and OHSU Institutional Review Boards. Written consent was obtained from all the participants. The study was registered on ClinicalTrials.gov (NCT01188811) and conducted following 2010 CONSORT guidelines. Study personnel roles. The PI conducted screening visits and initial EDSS examinations for randomization, evaluated adverse events (AEs), and served as the study monitor. Blinded neurologists and a neurology advanced practitioner served as EDSS examiners. Blinded study coordinators collected mobility data, questionnaires, and maintained databases. Investigational drug. An Investigational New Drug indication was obtained by the PI (no. 110132). Pure Encapsulations (Sudbury, MA) provided gelatin capsules containing 600 mg racemic LA or placebo. Placebo capsules contained Avicel (microcellulose crystal) and 4.3 mg of quercetin (a bioflavonoid) that rendered the placebo a yellow color, similar to LA. Expiration of the study drug was extended once during the study by Pure Encapsulations after retesting of sample capsules determined continued stability. Study timeline. Screen and baseline visits were#30 days apart. Subsequent visits at months 3, 6, 12, 18, and 24 occurred 62 weeks. A month was defined as 4 weeks for scheduling purposes. MRI and OCT occurred at baseline, months 12 and 24. Clinical outcome measures were collected at baseline and every 6 months. Safety laboratory measures were performed at each visit. Telephone calls occurred between visits and after study completion to capture AEs. Outcomes. Primary outcome was difference in annual percent change brain volume (PCBV) on MRI by Structural Image Evaluation, using Normalisation, of Atrophy (SIENA). Secondary outcomes included atrophy rates of segmented brain, spinal cord, and retinal substructures, changes in disability, quality of life, and safety. MRI acquisition protocol. MRI acquisition and analyses details are shown in appendix e-1 at Neurology.org/nn. The following sequences were acquired using a Philips Achieva 3.0T X-series with Quasar Dual gradient systems: (1) 3D highresolution magnetization-prepared rapid acquisition gradient echo (3D MP-RAGE) with 1 mm voxels for high-resolution structural (T1-weighted) information. The upper cervical spinal cord was intentionally included in the series through positioning; (2) 3D fluid-attenuated inversion recovery (3D FLAIR) series with 1 mm voxels; (3) conventional 3 mm (0.3 gap) axial 2D proton density/T2-weighted sequences with in-plane resolution 1 mm; and (4) 3-mm sagittal 2D proton density/T2-weighted spinal cord sequences. No intravascular contrast was used. MRI analyses. MRIs were reviewed by a neuroradiologist for unexpected findings. A single trained MRI analyst performed lesion counts, volumetrics, and cortical thickness analyses. The 2 Neurology: Neuroimmunology & Neuroinflammation PI conducted spinal cord cross-sectional thickness and lesion occupancy analyses. Both were directed by the study neuroradiologist. Cerebral T2-hyperintense lesion volumes and maps were obtained using Lesion TOpology-preserving Anatomical Segmentation (Lesion-TOADS). FSL tools were used to create lesion-filled MP-RAGE images. SIENAX was used to determine cross-sectional whole-brain, white, and grey matter volumes. Whole-brain atrophy was determined using SIENA from the FSL package. Subcortical deep grey matter volumes were measured using FIRST. Cortical thickness, cortical volumetric segmentation, and analyses of these were performed with FreeSurfer (surfer.nmr.mgh.harvard.edu/) and its longitudinal processing stream. Spinal cord cross-sectional area was recorded at C1. An in-house estimation of the relative percent of the spinal cord from the foramen magnum to the lower edge of C7 occupied by MS lesions was devised for descriptive purposes. MRIs were graded for quality (good, fair, poor, and unusable). Poor and unusable scans were excluded from the analyses. OCT. Participants underwent spectral domain OCT (Cirrus HDOCT; Carl Zeiss Meditec, Inc., Dublin, CA) in each eye after pharmacologic dilation (1% tropicamide and 0.5% proparacaine hydrochloride). Peripapillary and macular scans were obtained with Optic Disc Cube 200 3 200 and Macular Cube 512 3 128 protocols, respectively. OCTs were reviewed by an experienced neuro-ophthalmologist. Excluded scans had confounding findings, artifact, misalignment, or signal strength less than 7. Clinical measures. Disability was captured by the EDSS. The same EDSS examiner was used for a given participant throughout the study to the extent possible. Mobility measures for ambulatory participants were Timed 25-Foot Walk (T25FW), Multiple Sclerosis Walking Scale (MSWS-12) Questionnaire, and Activities-specific Balance Confidence (ABC) Questionnaire. Symbol Digit Modalities Test (SDMT) tested cognition. RAND 36-Item Short Form Health Survey assessed quality of life. Safety monitoring. AEs were categorized using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Unscheduled visits occurred for relapses, AEs, and early study termination visits. Safety monitoring laboratory tests (complete blood count and kidney and liver panels) were checked at each visit. The Columbia-Suicide Severity Rating Scale (C-SSRS) was administered at every visit. A 3-member data safety and monitoring board met every year. Sample size, randomization, and blinding. The study was powered for comparison of the primary outcome, PCBV, as Figure 1 2010 CONSORT flow diagram Neurology: Neuroimmunology & Neuroinflammation 3 estimated by Altmann et al. using an SD of 1.51 for SIENA atrophy, 2-year study length with yearly MRIs, and 60% effect size. A sample size of 23 per arm was needed to obtain 80% power and a significance of p , 0.05. Projected enrollment was increased to allow for dropouts. Participants were assigned to LA or placebo in a 1:1 manner by the unblinded research pharmacist following a permutated block randomization based on EDSS #4.5 or .4.5. All other study personnel were blinded to the treatment assignment. MRIs were labeled with additional randomly generated numbers during analyses to further reduce the risk of bias. Statistical analysis was performed by a blinded statistician for primary, secondary, and safety outcome measures. Statistical methods. Intention-to-treat (ITT) analysis used linear mixed models to evaluate the effect of LA on annualized PCBV. Mixed models were used to adjust for withinparticipant serial correlation, to account for the repeated measurements of the longitudinal design, and to include all study participants. Models were corrected for participant age, sex, and MS duration with standard model diagnostics to identify overly influential leverage points. Multiple comparisons were accounted for using the Holm-Sidak correction within the study outcome domains. Outlier data points were identified through standard diagnostic techniques using combinations of data point leverage, individual residuals, and Cook distance to identify overly influential observations and exclude them from baseline and 2-year change analyses. Data from participants taking a reduced dose of LA (n 5 2) were not handled differently in outcome analyses as their limited number made subgroup assessment intractable. Mixedmodel results are reported as rates of change with variance represented by the standard errors of the coefficient estimates (SEEs). Post hoc analysis of the primary outcome measure was conducted adding the baseline whole-brain volume and baseline T2-lesion volume as covariates to the model. All analyses were performed using R 3.3.1 with additional utility from the lme4 package. RESULTS Of the 54 consented and randomized, 51 participants (27 LA and 24 placebo) took at least 1 dose of study drug and were included in the ITT analyses (figure 1). Forty-six participants completed the study (22 LA and 24 placebo). The 5 dropouts in the LA cohort were for reasons of claustrophobia during MRI, prolonged nausea and vomiting which resolved on cessation of LA, and significant concurrent illness (prostate cancer, proteinuria, and worsening renal function). Because the dropout with claustrophobia did not complete the baseline MRI, the LA cohort ITT sample size for PCBV was 26 (figure 1). Baseline demographics are presented in table 1. The LA and control cohorts were overall matched for age, sex, MS duration, education, and disability. There were no significant differences between treatment arms (all p . 0.05). Table 2 presents the baseline values of the main study outcome measures by study arms. The LA cohort had a significantly larger baseline whole-brain (p 5 0.004) and total deep grey matter volumes (p 5 0.042). Controls had larger baseline normalized T2-lesion volumes. Compliance with study drug was 87% by pill counts. Two participants took a halved dose of LA per protocol for the majority of the study, one each for gastritis and elevated alkaline phosphatase levels. Rate of brain atrophy and secondary imaging outcomes. After 2 years, participants taking LA had significantly less annualized PCBV (20.21% [SEE 0.14]) than controls (20.65% [SEE 0.10], p 5 0.002), with the beneficial effect size of LA treatment observed to be a 0.44% 6 0.29% improvement in the rate of whole-brain atrophy (95% confidence interval [CI] 0.157–0.727). This change corresponds to a 68% reduction in the rate of brain atrophy in LA vs placebo (figure 2A, table 3). In post hoc analysis, baseline whole-brain volume was not associated with any of the other controlling covariates (age, sex, and disease duration), nor did it affect the differences in PCBV between the study cohorts. Likewise, T2Table 1 Baseline demographics and clinical characteristics of study participants by treatment (n 5 51) LA (n 5 27) Placebo (n 5 24) No. or median SD, %, or IQR (range) No. or median SD, %, or IQR (range) Age, y 57.9 6.7 59.7 6.0