A randomized clinical trial of lithium in multiple system atrophy

Saccà, Francesco; Marsili, Angela; Quarantelli, Mario; Morra, V. Brescia; Brunetti, Arturo; Carbone, Rosa; Pane, Chiara; Puorro, Giorgia; Russo, Cinzia Valeria; Salvatore, Elena; Tucci, Tecla; Michele, Giuseppe De; Filla, Alessandro

doi:10.1007/s00415-012-6655-7

Cited by 36 publications

(28 citation statements)

References 13 publications

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“…We found no placebo-controlled trials assessing rifampicin in patients with multiple system atrophy, but we did find five double-blind, placebo-controlled clinical trials assessing long-term effects of other interventions 29,31–34 and one recent report (a double-blind, placebo-controlled study) of rasagiline in multiple system atrophy 30 (abstract only). All were either inconclusive (growth hormone, 34 primary endpoint of Unified Parkinson’s Disease Rating Scale, n=43), negative (minocycline, 32 primary endpoint of Unified Multiple System Atrophy Rating Scale [UMSARS] II, n=60; rasagiline, 30 UMSARS I+II, n=174), or terminated prematurely (riluzole, 33 primary endpoint of survival, n=760; lithium, 29 primary endpoint of adverse events, n=9), except for the study on mesenchymal stem cells 31 (primary endpoint of UMSARS I and II, n=33). We did not include four small studies that aimed to assess short-term symptomatic effects (paroxetine, 35 riluzole, 36 amantadine, 37 and occupational therapy 38 ) and a randomised but open-label study (oestrogen in combination with buspirone 39 ) in our review.…”

Section: Figurementioning

confidence: 83%

“…Previous double-blind, placebo-controlled trials targeting progression of multiple system atrophy with lithium, 29 rasagiline, 30 mesenchymal stem cells, 31 minocycline, 32 riluzole, 33 and growth hormone 34 have been largely unsuccessful (panel). Mesenchymal stem cells were reported to delay progression of multiple system atrophy significantly in a single-centre study of 33 patients with cerebellar multiple system atrophy, 31 but this study required intracarotid and intravertebral infusions, and cerebral ischaemia was a potential safety issue.…”

Section: Discussionmentioning

confidence: 99%

“…Mesenchymal stem cells were reported to delay progression of multiple system atrophy significantly in a single-centre study of 33 patients with cerebellar multiple system atrophy, 31 but this study required intracarotid and intravertebral infusions, and cerebral ischaemia was a potential safety issue. 40 Two studies were terminated before completion, one for toxicity (lithium) 29 and the other for ineffectiveness (riluzole), 33 and the others were inconclusive (growth hormone) 34 or negative (minocycline, rasagiline). 30,32 A randomised open-label study of oestrogen in combination with buspirone 39 was also negative.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial

Low

Robertson

Gilman

et al. 2014

The Lancet Neurology

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Summary Background No available treatments slow or halt progression of multiple system atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of multiple system atrophy, rifampicin inhibited formation of α-synuclein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with multiple system atrophy. Methods In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30–80 years with possible or probable multiple system atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221. Findings Between April 22, 2011, and April 19, 2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0·62 points [SD 0·85] per month in the rifampicin group vs 0·47 points [0·48] per month in the placebo group; futility p=0·032; efficacy p=0·76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0·5 points (SD 0·7) per month for rifampicin and 0·5 points (0·5) per month for placebo (difference 0·0, 95% CI –0·24 to 0·24; p=0·82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment. Interpretation Our results show that rifampicin does not slow or halt progression of multiple system atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with multiple system atrophy. Funding National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds.

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Section: Figurementioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial

Low

Robertson

Gilman

et al. 2014

The Lancet Neurology

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“…A randomized, double-blind, placebo-controlled study was performed to assess the safety and tolerability of lithium, a candidate neuroprotective therapy for MSA, however, the trial had to be terminated due to severe adverse effects (Sacca et al, 2013). …”

Section: Disease Modification Strategiesmentioning

confidence: 99%

Towards translational therapies for multiple system atrophy

Kuzdas-Wood

Stefanova

Jellinger³

et al. 2014

Progress in Neurobiology

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“…Therefore, a randomized clinical trial of lithium in 9 MSA patients was performed in Italy 58 . All patients in the lithium group abandoned because of adverse effects except for one who died.…”

Section: Potential Therapeutic Targets In Msamentioning

confidence: 99%

Novel therapeutic approaches in multiple system atrophy

Palma

2014

Clin Auton Res

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Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly, progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of α-synuclein–containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic α-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprise cell-to-cell transmission of α-synuclein in a prion-like manner, α-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of α-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflamatory drugs, which inhibit α-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchimal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review.

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A randomized clinical trial of lithium in multiple system atrophy

Cited by 36 publications

References 13 publications

Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial

Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial

Towards translational therapies for multiple system atrophy

Novel therapeutic approaches in multiple system atrophy

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