TY - JOUR
T1 - Davunetide in patients with progressive supranuclear palsy
T2 - A randomised, double-blind, placebo-controlled phase 2/3 trial
AU - Boxer, Adam L.
AU - Lang, Anthony E.
AU - Grossman, Murray
AU - Knopman, David S.
AU - Miller, Bruce L.
AU - Schneider, Lon S.
AU - Doody, Rachelle S.
AU - Lees, Andrew
AU - Golbe, Lawrence I.
AU - Williams, David R.
AU - Corvol, Jean Cristophe
AU - Ludolph, Albert
AU - Burn, David
AU - Lorenzl, Stefan
AU - Litvan, Irene
AU - Roberson, Erik D.
AU - Höglinger, Günter U.
AU - Koestler, Mary
AU - Jack, Clifford R.
AU - Van Deerlin, Viviana
AU - Randolph, Christopher
AU - Lobach, Iryna V.
AU - Heuer, Hilary W.
AU - Gozes, Illana
AU - Parker, Lesley
AU - Whitaker, Steve
AU - Hirman, Joe
AU - Stewart, Alistair J.
AU - Gold, Michael
AU - Morimoto, Bruce H.
N1 - Funding Information:
The study was sponsored by Allon Therapeutics (Vancouver, BC, Canada), which was purchased by Paladin Laboratories in August, 2013. The study was designed by an academic steering committee in collaboration with the sponsor. The sponsor funded data gathering, the planned analyses, and an initial interpretation of the data. All authors had full access to the data, no medical writer or editor was employed, and the decision to submit the manuscript was made by the authors without input from any corporate entity. All authors had final responsibility for the decision to submit the paper for publication.
PY - 2014/7
Y1 - 2014/7
N2 - Background: 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. Methods: 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. Findings: 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%]). Interpretation: 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. Funding: Allon Therapeutics.
AB - Background: 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. Methods: 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. Findings: 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%]). Interpretation: 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. Funding: Allon Therapeutics.
UR - http://www.scopus.com/inward/record.url?scp=84902545124&partnerID=8YFLogxK
U2 - 10.1016/S1474-4422(14)70088-2
DO - 10.1016/S1474-4422(14)70088-2
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AN - SCOPUS:84902545124
SN - 1474-4422
VL - 13
SP - 676
EP - 685
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 7
ER -