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Services for preclinical_and_clinical_trials


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  • 1. The Siesta Group Services for S fPreclinical and Clinical Trials
  • 2. The companyClinical trial service providerspecialised in sleep and/orElectroencephalography (EEG)Large scientific background,p yphysician co-ownedTight network of partners andassociatesHeadquarter :Vienna, Austria, EuropeUS operations through Philips-RespironicsDeveloper of Somnolyzer24x7,purchased by Philips Respironics Philips-Respironics,Feb 2010 2
  • 3. Target areas We offer solutions for trials on CNS-active drugs th t d that have a focus on measurement of sleep, vigilance, sleep-wake cycles, wether as primary, secondary l k l th i d or exploratory endpoints have a focus on measurements of brain activity with pharmaco-EEG (electroencephalography) generally include polysomnography (PSG) (PSG), actigraphy, sleep diaries, vigilance tests, or EEG In all phases from preclinical to phase IV phases, 3
  • 4. Services we offer Consulting and protocol development Trial feasibility and set-up Ti lf ibilit d t Site identification, preparation, training, management Centralized data C t li d d t analysis, such as sleep scoring, l i h l i EEG spectral analysis, and other endpoint calculation PSG and EEG data quality monitoring and q alit harmonization Biomarker research and exploratory data analysis Device rentals 4
  • 5. Our USPs – your advantage State-of-the-art data analysis technology, including the world s most reliable sleep scoring system world‘s system, Somnolyzer 24x7 Efficient internet-based communication for quick turn- internet based turn arounds Top-of-the-line sleep and EEG experts for ultimate Top of the line know-how Flexibility and responsiveness during complex trials y p g p Translational data analyis, support throughout a drug‘s development cycle 5
  • 6. The Siesta GroupClinical Trial Services1. Scoring and data anaylsis for single and multi-site g trials 6. Phase I unit WITH PARTNER JSW Lifesciences2. Quality control and monitoring3. Site & Project management CORE BUSINESS (with partner JSW)4. Investigator site(s) and global networks 6
  • 7. Core technology sleep: Somnolyzer 24x7Computer supported analysis of polysomnography (PSG): Sleep staging / sleep architecture Respiratory analysis PLM analysis Arousal analysis Spindle and K-complex analysis Artefact detection FFT analysis (incl. Pharmaco-EEG) New ways of describing sleep (innovative biomarkers) Norm data comparisonsReliable, validated, according to published standards , , g p(incl. latest AASM standards) 7
  • 8. Siesta Somnolyzer 24x7Raw Data EDF Raw Data Quality Check EMG-(sub)mental EDF-header EOG-left EOG l f & right i h Artifact id ifi i A if identification EEG-central Rejection of the unknownFeature Matrix Feature Extraction 101 features per EEG: Background and pattern 30-s epoch EOG: slow and rapid EM Quality Manager ASCII EMG: tonic and phasic Visual editing Feature Matrix Plausibility Check Feature distribution R&K Scores Classification Siesta Spot Report Expert system: Table and graphics Hypnogram Explicit and implicit knowledge p p g PDF EDF Smoothing rules R&K Scores Hypnogram EDF Siesta Spot Report R t Report Generation Table and graphics Comparison to normative values PDF 8
  • 9. Overall performace(validation set, N=285; 270,100 epochs) 100 90 80 70 60 50 99.4 87.6 40 76.9 77.2 76.1 79.6 30 20 10 0 Scoring 1 Somnolyze r Somnolyze r Somnolyze r Somnolyze r Somnolyze r v s. Scoring 2 24x7 v s. Scoring 24x7 v s. Scoring 24x7 v s. 24x7 v s. Scoring 24x7: QM 1 v s. 1 2 Conse nsus 1 or 2 or QM 2 Scoring Conse nsusAnderer et al., Neuropsychobiology 2005;51(3):115-33 9
  • 10. Advantages of computer supported analysis Issues in PSG Computer supported analsyis Variance in PSG scoring g Very low variance in scoring y g Interrater agreement Over 98% reliability around 75% Increases power of Delay in scoring significance tests Difficulty for screening No delay in scoring and dosing decisions Same day decisions, for Deviations from standard screening, dosing, etc. (montage, filter settings, Trial results immediately etc.) etc ) after LPLV Non-homogenous data in Full abidance to standard multi-center trials Ensuring homogenous data Difficult quality q y AASM and R&K maintenance, artefacts Quality monitoring Loss of information, loss Minimum loss of information of data Clean data sets EDF as pseudo-standard pseudo standard Much M h more cost-efficient t ffi i t Costly From feasibility to study 10 conduct
  • 11. References Anderer P, Gruber G, Parapatics S, et al.: An E-health solution for automatic sleep classification according to Rechtschaffen and Kales: validation study of the Somnolyzer 24 x 7 utilizing the Siesta database. Neuropsychobiology. y g p y gy 2005;51(3):115-33. Validation on almost 300 PSGs Dorffner G, Woertz M, Anderer P et al.: Validation of an automatic detection system of breathing events during sleep, Sleep 2007;30, abstract supplement, y g g p p pp A355. Penzel T, Hirshkowitz M, Harsh J, et al. Digital analysis and technical specifications, Journal of Clinical Sleep Medicine 2007;3(2)109-120. Lists Somnolyzer 24x7 as the top “grade 1” autoscoring solution Svetnik V, Ma J, Soper K, et al.: Evaluation of automatic and semi-automatic scoring of polysomnographic recordings from a clinical trial using Zolpidem in the treatment of insomia, Sleep, 2007 Nov;30(11):1562-74. Independent validation on clinical trial data Hoever P, Dorffner G, Beneš H, Penzel T, Danker-Hopfe H, Barbanoj MJ, Pillar G, Saletu B, Polo O, Kunz D, Zeitlhofer J, Berg S, Partinen M, Bassetti CL, Högl B, Ebrahim IO, Holsboer-Trachsler E, Bengtsson H, Peker Y, Hemmeter UM, Chiossi E, Hajak G, Dingemanse J.: Orexin Receptor Antagonism, a New Sleep- Enabling Paradigm: A Proof-of-Concept Clinical Trial Clin Pharmacol Ther Proof of Concept Trial, Ther. 2012 Jun;91(6):975-85. Somnolyzer in a successful PoC trial 11
  • 12. Core technologies: Pharmaco-EEG Single channel topography tomography (LORETA) pectral nalysisSpan elated 3 2 1 t-values Potntials 0 -1 -2Event-re -3 N1- P2- N2- P300- LATENCY LATENCY LATENCY LATENCYE 12
  • 13. Pharmaco-EEG: main applications classification of psychotropic drugs demonstration of the time course of the cerebral bioavailability of a psychotropic drug at its target organ – the human brain demonstration of dose efficacy relations dose-efficacy exploration of bioequipotency exploration of pharmacokinetic/pharmacodynamic relationships exploration of the relationship between CNS effectiveness and therapeutic efficacy (pharmaco- (pharmaco EEG as a predictive model) therapeutic monitoring of patients or patient groups 13
  • 14. Pharmaco-EEG: Our strengths Covering full spectrum of pharmaco-EEG High level quality control Superior artefact treatment 30 years of experience State-of-the-art technology gy Top experts in psychiatry and neurology Following latest IPEG standards 14
  • 15. Selected ReferencesSaletu B, Anderer P, Saletu-Zyhlarz GM. EEG topography and tomography(LORETA) in diagnosis and pharmacotherapy of depression. Clin EEG Neurosci.2010 Oct;41(4):203-10. ; ( )Saletu M, Anderer P, Saletu-Zyhlarz GM, Mandl M, Saletu B, Zeitlhofer J.Modafinil improves information processing speed and increases energeticresources for orientation of attention in narcoleptics: double-blind, placebo-controlled ERP studies with low-resolution brain electromagnetic tomography g g p y(LORETA). Sleep Med. 2009 Sep;10(8):850-8.Anderer P, Saletu B, Wolzt M, Culic S, Assandri A, Nannipieri F, Rosini S, Saletu-Zyhlarz GM. Double-blind, placebo-controlled, multiple-ascending-dose study onthe effects of ABIO-08/01, a novel anxiolytic drug, on perception and cognition,utilizing event-related potential mapping and l tili i t l t d t ti l i d low-resolution b i electromagnetic l ti brain l t titomography. Hum Psychopharmacol. 2008 Apr;23(3):243-54.Anderer P, Saletu B, Gruber D, Linzmayer L, Semlitsch HV, Saletu-Zyhlarz G,Brandstätter N, Metka M, Huber J. Age-related cognitive decline in themenopause: effects of hormone replacement therapy on cognitive event related event-relatedpotentials. Maturitas. 2005 Jul 16;51(3):254-69.Anderer P, Semlitsch HV, Saletu B, Saletu-Zyhlarz G, Gruber D, Metka M, HuberJ, Gräser T, Oettel M. Effects of hormone replacement therapy on perceptual andcognitive event related potentials in menopausal insomnia event-related insomnia.Psychoneuroendocrinology. 2003 Apr;28(3):419-45. 15
  • 16. Service Level 1 & 2 :Scoring / reading center Sleep: PSG, actigraphy, psychometric tests, etc. Pharmaco EEG: Pharmaco-EEG: Spectral analysis mapping LORETA analysis, mapping, LORETA, event-related potentials Scoring (reading), endpoint calculation, statistical analysis Process harmonization and data quality monitoring Remote or on-site training on site Advantages: Reliable data analysis (low variance) Fast responses ( g for screening decisions) p (e.g. g ) Immediate quality control Raw data handling by the EDF experts 16
  • 17. Scoring/Reading center – data flow Endpoint variable Sponsor tableCRF S esta Siesta reports Online SDex PSG/EEG data (edf) Inv. site Inv. siteMain variables Inv. site Secure ftp Inv. Inv site 17
  • 18. Services Level 3 & 4: S i L l 4 Site and Project Management • CTA • CRF Sponsor •ddrug shipment hi t • randomization • statistics Main contract • site selection and feasibility Siesta • main study files and materials • study guidelines JSW Lifesciences subcontract • investigator and initiation meetings• HA and EC/IRB • project management p j g submission Inv. site • timeline and recruitment Inv. site monitoring (online!)• initiation Inv. site• monitoring Inv. Inv site • financial administration• Data management 18
  • 19. Siesta Investigator Network Europe: 30 E 30+ (Austria, Germany, Switzerland, Netherlands, Scandinavia, France, Spain, UK) North America: 10+ Other regions: 10+ (Israel, Australia, South Africa, South America) Continuously expanding 19
  • 20. Preclinical Research Working with top experts and animal facilities, The Siesta Group can be your partner for Consulting on protocols Efficiently conducting single or multi-dose protocols in select y g g p animal groups Scoring animal EEG and sleep Exploratory analysis of data to identify differentiating drug effects Integrative/translational approach From preclinical research, via phase I to late-phase clinical trials p 20
  • 21. Additional services:Consulting and support Consulting on study protocol Rental, or support with purchase, of equipment Retrospective data analysis Biomarker research Scientific writing Advantages: Access to experts with >20 years of experience in sleep trials Network of sleep labs Close contacts to equipment manufacturers State-of-the-art signal processing High reputation scientists 21
  • 22. Norm data comparison ** 100 ** ** ** * 90 * ** 80 70 Sle efficiency (in % TIB) 60 n Placebo 50 Treatment Normal Controls 40 eep 30 20 10 0 Total night First quarter Second Third Fourth quarter quarter quarter Key-lock-principle (Saletu) Ke lock principle (Salet ) 22
  • 23. Core medical partners and references Michael Decker, PhD Georgia State University, Atlanta, GA Hartmut Schneider Naresh Punjabi Alan Schwartz, MD Schneider, Punjabi, Schwartz Johns Hopkins University, Baltimore, MD Riccardo Stoohs, MD Stanford University, CA Joseph Golish MD Golish, Cleveland, OH Martin King LCG Biosciences, UK Bernd Saletu MD; Josef Zeitlhofer MD PhD Saletu, Zeitlhofer, Medical University of Vienna, Austria Dieter Kunz, MD, Heidi Danker-Hopfe, PhD; Thomas Penzel, PhD; Charité University Medicine, Berlin, Germany Manel Barbanoj, MD † Barbanoj University of Barcelona, Spain Bob Kemp, PhD Holland Sleep Research, The Hague, Netherlands Irshaad Ebrahim, I h d Eb hi MD London Sleep Center, UK 23
  • 24. Experience Scoring center > 25 Phase I and II + device trials Insomnia, narcolepsy, RLS, OSAS, schizophrenia, others Europe and USA Site and project management 2 Phase I and II Insomnia, narcolepsy Europe References: Insomia phase Ib, Orexin receptor anatgonist, Actelion, CH Restless L S d R tl Leg Syndrome phase II D h II, Dopamine agonist, i i t Neurogen, USA 24
  • 25. Seamless cooperation with other CROs Trial management: g p Sponsor overall negotiation, regulatory and legal assistance CRO CRFs, monitoring, drug handling, randomization Protocol implementation, site and patient recruitment project management, data q p j g quality control y Data analysis, TSG On-site support pp endpoints in compliant data format Biostatistics, report and presentation Bi t ti ti t d t ti 25
  • 26. Our motto Measurement of EEG and sleep is a most complex matter Make it simple by working with the experts 26
  • 27. Contact The Siesta Group Vienna, Vienna Austria: Phone: +43 1 9551213 @ g p USA: Philips Respironics Bend, Oregon: Phone: 1-541-598-3800, 1-800-685-2999 clinicaltrials respironics com 27