2. The company
Clinical trial service provider
specialised in sleep and/or
Electroencephalography (EEG)
Large scientific background,
p y
physician co-owned
Tight network of partners and
associates
Headquarter :
Vienna, Austria, Europe
US operations through Philips-
Respironics
Developer 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 Group
Clinical Trial Services
1. Scoring and data anaylsis
for single and multi-site
g
trials 6. Phase I unit
WITH PARTNER
JSW Lifesciences
2. Quality control and
monitoring
3. Site & Project management CORE BUSINESS
(with partner JSW)
4. Investigator site(s) and
global networks 6
7. Core technology sleep: Somnolyzer 24x7
Computer 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 comparisons
Reliable, validated, according to published standards
, , g p
(incl. latest AASM standards)
7
8. Siesta Somnolyzer 24x7
Raw 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 unknown
Feature 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 nsus
Anderer 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
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 References
Saletu 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 energetic
resources 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 on
the 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 ti
tomography. 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 the
menopause: effects of hormone replacement therapy on cognitive event related
event-related
potentials. Maturitas. 2005 Jul 16;51(3):254-69.
Anderer P, Semlitsch HV, Saletu B, Saletu-Zyhlarz G, Gruber D, Metka M, Huber
J, Gräser T, Oettel M. Effects of hormone replacement therapy on perceptual and
cognitive 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 table
CRF
S esta
Siesta
reports
Online SDex
PSG/EEG data (edf)
Inv. site
Inv. site
Main 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
info@thesiestagroup.com
@ g p
www.thesiestagroup.com
USA: Philips Respironics
Bend, Oregon:
Phone: 1-541-598-3800, 1-800-685-2999
respironics.minimitter@philips.com
clinicaltrials.respironics.com
clinicaltrials respironics com
27
