PROSPERA: a randomized, controlled trial evaluating rasagiline in progressive supranuclear palsy
- 686 Downloads
To date, pharmacological treatment options for progressive supranuclear palsy (PSP), a neurodegenerative tauopathy, are limited. The MAO-B inhibitor rasagiline has shown neuroprotective effects in preclinical models of neurodegeneration. To evaluate the safety, tolerability and therapeutic effect of rasagiline on symptom progression in PSP. In this 1-year randomized, double-blind, placebo-controlled trial, 44 patients fulfilling the NINDS-PSP criteria were randomized to 1 mg/d rasagiline or placebo. The combined primary endpoint included symptom progression as measured by the PSP rating scale (PSP-RS) and the requirement of L-dopa rescue medication. Secondary endpoints included Schwab and England Activities of Daily Living (SEADL), Montgomery–Åsberg Depression Rating Scale, Mini Mental State Examination, Frontal Assessment Battery and posturographic measurements. Of the 44 patients randomized, 26 completed the trial per protocol. Rasagiline was well tolerated, with a slight increase of known side effects (hallucinations, ventricular extrasystoles). No effect on the primary endpoint (p = 0.496) was detected. Symptom progression averaged at 11.2 (rasagiline) and 10.8 (placebo) points per year (ΔPSP-RS). No difference was seen in SEADL, depression, cognitive function, frontal executive function and posturographic measurements. Post hoc analyses of PSP-RS subdomains indicate a potential beneficial effect in the “limb motor” subdomain, whereas performance appeared lower in the “mentation” and “history” subdomains in the treatment group. While rasagiline is well tolerated in PSP, a beneficial effect on overall symptom progression was not detected. Post hoc analyses suggest the implementation of more specific endpoints in future studies.
KeywordsProgressive supranuclear palsy Rasagiline Tauopathy Clinical trial
The authors thank Carina Abright and Dr. Stefan Kammermeier for additional data collection as well as Dr. Siegbert Krafczyk (Klinikum der Universität München, Munich, Germany) for excellent technical assistance concerning posturographic measurements. This investigator-initiated trial was sponsored by TEVA pharmaceutics (Petah Tikva, Israel).
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflict of interest. Prof. Stefan Lorenzl received honoraria from UCB, TEVA, Orion, Boehringer Ingelheim and Gruenenthal not related to this study. He serves as an advisory board member for UCB. The investigator-initiated trial presented here was sponsored by TEVA pharmaceutics (Petah Tikva, Israel). The decision to publish this article was solely the responsibility of the authors. All statements, opinions, and content presented in the published article are those of the authors and do not represent the opinions of Teva. Teva provided a medical accuracy review of the article.
The study protocol, patient information and consent form were reviewed by an internal review board (application number 344-09). The trial was conducted according to international GCP standards (ICH guidelines and the Helsinki Declaration). Prior to inclusion, written informed consent was obtained from all participants or their caregivers, respectively. This trial was registered to clinicaltrials.gov (NCT01187888).
- 7.Naoi M, Maruyama W, Yi H (2013) Rasagiline prevents apoptosis induced by PK11195, a ligand of the outer membrane translocator protein (18 kDa), in SH-SY5Y cells through suppression of cytochrome c release from mitochondria. J Neural Transm 120(11):1539–1551. doi: 10.1007/s00702-013-1033-x CrossRefPubMedGoogle Scholar
- 9.Litvan I, Agid Y, Jankovic J, Goetz C, Brandel JP, Lai EC, Wenning G, D’Olhaberriague L, Verny M, Chaudhuri KR, McKee A, Jellinger K, Bartko JJ, Mangone CA, Pearce RK (1996) Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). Neurology 46(4):922–930CrossRefPubMedGoogle Scholar
- 12.Schwab RS, England AC (1969) Projection technique for evaluating surgery in Parkinson’s Disease. Paper presented at the 3rd symposium on Parkinson’s Disease, Edinburgh, ScotlandGoogle Scholar
- 13.Riedel O, Dodel R, Deuschl G, Forstl H, Henn F, Heuser I, Oertel W, Reichmann H, Riederer P, Trenkwalder C, Wittchen HU (2011) Dementia and depression determine care dependency in Parkinson’s disease: analysis of 1,449 outpatients receiving nursing care in Germany. Nervenarzt 82(8):1012–1019. doi: 10.1007/s00115-010-3186-2 CrossRefPubMedGoogle Scholar
- 15.Stamelou M, Schope J, Wagenpfeil S, Del Ser T, Bang J, Lobach IY, Luong P, Respondek G, Oertel WH, Boxer A, Hoglinger GU, Al-108-231 Investigators TI, Group MD-EPS (2016) Power calculations and placebo effect for future clinical trials in progressive supranuclear palsy. Mov Disord. doi: 10.1002/mds.26580 Google Scholar
- 20.Schrag A, Barone P, Brown RG, Leentjens AF, McDonald WM, Starkstein S, Weintraub D, Poewe W, Rascol O, Sampaio C, Stebbins GT, Goetz CG (2007) Depression rating scales in Parkinson’s disease: critique and recommendations. Mov Disord 22(8):1077–1092. doi: 10.1002/mds.21333 CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Zwergal A, la Fougere C, Lorenzl S, Rominger A, Xiong G, Deutschenbaur L, Linn J, Krafczyk S, Dieterich M, Brandt T, Strupp M, Bartenstein P, Jahn K (2011) Postural imbalance and falls in PSP correlate with functional pathology of the thalamus. Neurology 77(2):101–109. doi: 10.1212/WNL.0b013e318223c79d CrossRefPubMedGoogle Scholar
- 23.Boxer AL, Lang AE, Grossman M, Knopman DS, Miller BL, Schneider LS, Doody RS, Lees A, Golbe LI, Williams DR, Corvol JC, Ludolph A, Burn D, Lorenzl S, Litvan I, Roberson ED, Hoglinger GU, Koestler M, Jack CR Jr, Van Deerlin V, Randolph C, Lobach IV, Heuer HW, Gozes I, Parker L, Whitaker S, Hirman J, Stewart AJ, Gold M, Morimoto BH, Investigators AL (2014) Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet Neurol 13(7):676–685. doi: 10.1016/S1474-4422(14)70088-2 CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Zwergal A, la Fougere C, Lorenzl S, Rominger A, Xiong G, Deutschenbaur L, Schoberl F, Linn J, Dieterich M, Brandt T, Strupp M, Bartenstein P, Jahn K (2013) Functional disturbance of the locomotor network in progressive supranuclear palsy. Neurology 80(7):634–641. doi: 10.1212/WNL.0b013e318281cc43 CrossRefPubMedGoogle Scholar