Lipoic acid in secondary progressive MS

Spain, Rebecca; Powers, Katherine; Murchison, Charles; Heriza, Elizabeth; Winges, Kimberly M.; Yadav, Vijayshree; Cameron, Michelle; Kim, Ed; Horak, Fay B.; Simon, Jack H.; Bourdette, Dennis

doi:10.1212/nxi.0000000000000374

Cited by 107 publications

(45 citation statements)

References 32 publications

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“…In addition, the primary outcome progressed as expected in the placebo arm, in a similar way to what has been observed in other recent trials in SPMS. 13,101,109 Valuable information was obtained across the board for all secondary and exploratory measures, which will help to decide their place in future trial design as indicative and mechanistic measures.…”

Section: Fundingmentioning

confidence: 99%

Amiloride, fluoxetine or riluzole to reduce brain volume loss in secondary progressive multiple sclerosis: the MS-SMART four-arm RCT

et al. 2020

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Background Neuroprotective drugs are needed to slow or prevent neurodegeneration and disability accrual in secondary progressive multiple sclerosis. Amiloride, fluoxetine and riluzole are repurposed drugs with potential neuroprotective effects. Objectives To assess whether or not amiloride, fluoxetine and riluzole can reduce the rate of brain volume loss in people with secondary progressive multiple sclerosis over 96 weeks. The secondary objectives that were assessed were feasibility of a multiarm trial design approach, evaluation of anti-inflammatory effects, clinician- and patient-reported efficacy and three mechanistic substudies. Design A multicentre, multiarm, randomised, double-blind, placebo-controlled, parallel-group Phase IIb trial with follow-up at 4, 8, 12, 24, 36, 48, 72 and 96 weeks. Patients, investigators (including magnetic resonance imaging analysts), and treating and independent assessing neurologists were blinded to the treatment allocation. The target sample size was 440 patients. Setting Thirteen UK clinical neuroscience centres. Participants Participants were aged 25–65 years, had secondary progressive multiple sclerosis with evidence of disease progression independent of relapses in the previous 2 years, and had an Expanded Disability Status Scale score of 4.0–6.5. Patients were ineligible if they could not have a magnetic resonance imaging scan; had a relapse or steroids in the previous 3 months; or had epilepsy, depression, bipolar disorder, glaucoma, bleeding disorders or significant organ comorbidities. Exclusion criteria were concurrent disease-modified treatments, immunosuppressants or selective serotonin reuptake inhibitors. Interventions Participants received amiloride (5 mg), fluoxetine (20 mg), riluzole (50 mg) or placebo (randomised 1 : 1 : 1 : 1) twice daily. Main outcome measures The primary end point was magnetic resonance imaging-derived percentage brain volume change at 96 weeks. Secondary end points were new/enlarging T2 lesions, pseudoatrophy, and clinician- and patient-reported measures (including the Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Symbol Digit Modalities Test, low-contrast letter visual acuity, Multiple Sclerosis Impact Scale 29 items, version 2, Multiple Sclerosis Walking Scale, version 2, and questionnaires addressing pain and fatigue). The exploratory end points included measures of persistent new T1 hypointensities and grey matter volume changes. The substudies were advanced magnetic resonance imaging, optical coherence tomography and cerebrospinal fluid analyses. Results Between December 2014 and June 2016, 445 patients were randomised (analysed) to amiloride [n = 111 (99)], fluoxetine [n = 111 (96)], riluzole [n = 111 (99)] or placebo [n = 112 (99)]. A total of 206 randomised patients consented to the advanced magnetic resonance imaging substudy, 260 consented to the optical coherence tomography substudy and 70 consented to the cerebrospinal fluid substudy. No significant difference was seen between the active drugs and placebo in percentage brain volume change at week 96 as follows (where negative values mean more atrophy than placebo): amiloride minus placebo 0.0% (Dunnett-adjusted 95% confidence interval –0.4% to 0.5%), fluoxetine minus placebo –0.1% (Dunnett-adjusted 95% confidence interval –0.5% to 0.3%); riluzole minus placebo –0.1% (Dunnett-adjusted 95% confidence interval –0.6% to 0.3%). There was good adherence to study drugs. The proportion of patients experiencing adverse events was similar in the treatment and placebo groups. There were no emergent safety issues. Limitations There was a lower than expected uptake in the cerebrospinal fluid substudy. Conclusions A multiarm Phase II paradigm is efficient in determining which neuroprotective agents to take through to Phase III trials. Amiloride, fluoxetine and riluzole were not effective in reducing the brain atrophy rate in people with secondary progressive multiple sclerosis. Mechanistic pathobiological insight was gained. Future work To use the information gained from the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) to inform future trial design as new candidate agents are identified. Trial registration Current Controlled Trials ISRCTN28440672, NCT01910259 and EudraCT 2012-005394-31. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 3. See the NIHR Journals Library website for further project information. This trial also received funding from the UK MS Society and the US National Multiple Sclerosis Society.

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Section: Fundingmentioning

confidence: 99%

Amiloride, fluoxetine or riluzole to reduce brain volume loss in secondary progressive multiple sclerosis: the MS-SMART four-arm RCT

et al. 2020

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“…Although the primary endpoint (annualized brain percentage volume change) did not achieve statistical significance, however there was a significant relative reduction in brain atrophy in the AP group (36.5% as measured by SIENA, and 75% post hoc as measured by BPF, p = 0.033) compared to placebo. Recent phase 2 studies testing simvastatin [26], lipoic acid [27], ibudilast [28], and a novel multi-arm MS-SMART testing fluoxetine, amiloride or riluzole [29], have used brain atrophy as a biomarker of neurodegeneration to measure primary efficacy outcomes. In addition, our results can be compared with other progressive MS phase 2 trials, 48% of relative reduction with ibudilast [28] and 43% with simvastatin [26], also with similar rates in the placebo arms.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of andrographolide in not active Progressive Multiple Sclerosis: A prospective exploratory double-blind, parallel-group, randomized, placebo-controlled trial

Ciampi

Uribe-San-Martín

Cárcamo

et al. 2020

Preprint

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Background: Multiple sclerosis (MS) is a chronic immune mediated disease and the progressive phase appears to have significant neurodegenerative mechanisms. The classification of the course of progressive MS (PMS) has been re-organized into categories of active vs. not active inflammatory disease and the presence vs. absence of gradual disease progression. Clinical trial experience to date in PMS with anti-inflammatory medications has shown limited effect. Andrographolide is a new class of anti-inflammatory agent, that has been proposed as a potential drug for autoimmune disorders, including MS. In the present trial, we perform an exploratory pilot study on the efficacy and safety of andrographolide (AP) compared to placebo in not active PMS. Methods: A pilot clinical trial using 140mg oral AP or placebo twice daily for 24 months in patients with not active primary or secondary progressive MS was conducted. The primary efficacy endpoint was the mean percentage brain volume change (mPBVC). Secondary efficacy endpoints included 3-month confirmed disability progression (3-CDP) and mean EDSS change. Results: Forty-four patients were randomized: 23 were assigned to the AP group, and 21 were assigned to the placebo group. The median baseline EDSS of both groups was 6.0. Annualized mPBVC was -0.679% for the AP group and -1.069% for the placebo group (mean difference: -0.39; 95% CI [-0.836-0.055], p=0.08, relative reduction: 36.5%). In the AP group, 30% had 3-CDP compared to 41% in the placebo group (HR: 0.596; 95% CI [0.200 – 1.777], p=0.06). The mean EDSS change was -0.025 in the AP group and +0.352 in the placebo group (mean difference: 0.63, p=0.042). Adverse events related to AP were mild rash and dysgeusia. Conclusions: AP was well tolerated and showed a potential effect in reducing brain atrophy and disability progression, that need to be further evaluated in a larger clinical trial. Trial registration: ClinicalTrials.gov NCT02273635

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“…It has an excellent safety profile and has proven to be an effective therapy for EAE [ 30 , 32 , 35 , 43 ]. Furthermore, in a recent randomized, placebo-controlled phase II clinical study, brain volume loss over 2 years measured by magnetic resonance imaging was significantly reduced in SPMS under oral treatment with 1200 mg LA per day compared to placebo [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…A randomized controlled clinical trial evaluating the effect of 1200 mg LA per day for 12 weeks on the antioxidant capacity and serum cytokine profiles revealed an increased total antioxidant capacity [ 16 ] and a reduction of pro-inflammatory cytokines INF-γ, ICAM-1, TGF-β, and IL-4 in relapsing-remitting MS [ 17 ] while the serum levels of TNF-α, IL-6, and MMP-9 and the clinical expanded disability status scale (EDSS) score were unchanged. In a recent phase II clinical study on secondary progressive MS (SPMS), the annualized percent change of brain volume (PCBV) was significantly reduced in patients receiving LA compared to placebo (− 0.21 ± 0.14 vs − 0.65 ± 0.10) [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Early alpha-lipoic acid therapy protects from degeneration of the inner retinal layers and vision loss in an experimental autoimmune encephalomyelitis-optic neuritis model

Dietrich

Helling

Hilla

et al. 2018

J Neuroinflammation

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BackgroundIn multiple sclerosis (MS), neurodegeneration is the main reason for chronic disability. Alpha-lipoic acid (LA) is a naturally occurring antioxidant which has recently been demonstrated to reduce the rate of brain atrophy in progressive MS. However, it remains uncertain if it is also beneficial in the early, more inflammatory-driven phases. As clinical studies are costly and time consuming, optic neuritis (ON) is often used for investigating neuroprotective or regenerative therapeutics. We aimed to investigate the prospect for success of a clinical ON trial using an experimental autoimmune encephalomyelitis-optic neuritis (EAE-ON) model with visual system readouts adaptable to a clinical ON trial.MethodsUsing an in vitro cell culture model for endogenous oxidative stress, we compared the neuroprotective capacity of racemic LA with the R/S-enantiomers and its reduced form. In vivo, we analyzed retinal neurodegeneration using optical coherence tomography (OCT) and the visual function by optokinetic response (OKR) in MOG35–55-induced EAE-ON in C57BL/6J mice. Ganglion cell counts, inflammation, and demyelination were assessed by immunohistological staining of retinae and optic nerves.ResultsAll forms of LA provided equal neuroprotective capacities in vitro. In EAE-ON, prophylactic LA therapy attenuated the clinical EAE score and prevented the thinning of the inner retinal layer while therapeutic treatment was not protective on visual outcomes.ConclusionsA prophylactic LA treatment is necessary to protect from visual loss and retinal thinning in EAE-ON, suggesting that a clinical ON trial starting therapy after the onset of symptoms may not be successful.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1111-y) contains supplementary material, which is available to authorized users.

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Lipoic acid in secondary progressive MS

Cited by 107 publications

References 32 publications

Amiloride, fluoxetine or riluzole to reduce brain volume loss in secondary progressive multiple sclerosis: the MS-SMART four-arm RCT

Amiloride, fluoxetine or riluzole to reduce brain volume loss in secondary progressive multiple sclerosis: the MS-SMART four-arm RCT

Efficacy of andrographolide in not active Progressive Multiple Sclerosis: A prospective exploratory double-blind, parallel-group, randomized, placebo-controlled trial

Early alpha-lipoic acid therapy protects from degeneration of the inner retinal layers and vision loss in an experimental autoimmune encephalomyelitis-optic neuritis model

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