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Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial.

ABSTRACT: In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP.In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720.313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (-0·20 [-0·20 to -0·17] vs -0·20 [-0·22 to -0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [<1%]).Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments.Allon Therapeutics.

SUBMITTER: Boxer AL

PROVIDER: S-EPMC4129545 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial.

Boxer Adam L AL Lang Anthony E AE Grossman Murray M Knopman David S DS Miller Bruce L BL Schneider Lon S LS Doody Rachelle S RS Lees Andrew A Golbe Lawrence I LI Williams David R DR Corvol Jean-Cristophe JC Ludolph Albert A Burn David D Lorenzl Stefan S Litvan Irene I Roberson Erik D ED Höglinger Günter U GU Koestler Mary M Jack Clifford R CR Van Deerlin Viviana V Randolph Christopher C Lobach Iryna V IV Heuer Hilary W HW Gozes Illana I Parker Lesley L Whitaker Steve S Hirman Joe J Stewart Alistair J AJ Gold Michael M Morimoto Bruce H BH

The Lancet. Neurology 20140527 7

<h4>Background</h4>In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP.<h4>Methods</h4>In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placeb ...[more]

PMID: 24873720

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Project description:IntroductionProgressive supranuclear palsy (PSP) is a neurodegenerative disorder for which there are currently no disease-modifying therapies. The neuropathology of PSP is associated with the accumulation of hyperphosphorylated tau in the brain. We have previously shown that protein phosphatase 2 activity in the brain is upregulated by sodium selenate, which enhances dephosphorylation. Therefore, the objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying therapy for PSP.Methods and analysisThis will be a multi-site, phase 2b, double-blind, placebo-controlled trial of sodium selenate. 70 patients will be recruited at six Australian academic hospitals and research institutes. Following the confirmation of eligibility at screening, participants will be randomised (1:1) to receive 52 weeks of active treatment (sodium selenate; 15 mg three times a day) or matching placebo. Regular safety and efficacy visits will be completed throughout the study period. The primary study outcome is change in an MRI volume composite (frontal lobe+midbrain-3rd ventricle) over the treatment period. Analysis will be with a general linear model (GLM) with the MRI composite at 52 weeks as the dependent variable, treatment group as an independent variable and baseline MRI composite as a covariate. Secondary outcomes are change in PSP rating scale, clinical global impression of change (clinician) and change in midbrain mean diffusivity. These outcomes will also be analysed with a GLM as above, with the corresponding baseline measure entered as a covariate. Secondary safety and tolerability outcomes are frequency of serious adverse events, frequency of down-titration occurrences and frequency of study discontinuation. Additional, as yet unplanned, exploratory outcomes will include analyses of other imaging, cognitive and biospecimen measures.Ethics and disseminationThe study was approved by the Alfred Health Ethics Committee (594/20). Each participant or their legally authorised representative and their study partner will provide written informed consent at trial commencement. The results of the study will be presented at national and international conferences and published in peer-reviewed journals.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12620001254987).

Dataset Information

Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial.

Publications

Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial.

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