JiePieAward, Brussels
October 2nd, 2014
Clinical Research Strategies in MSA
Gregor K. Wenning MD PhD MSC
Division of Neurobiology
Department of Neurology & Neurosurgery
Medical University Innsbruck
AUSTRIA
florian.krismer@i-med.ac.at
EMSA Sites 10 / 2014
24 Study Sites in 12 EU
Countries + Israel
www.emsa-sg.org
EMSA Registry
Köllensperger et al., 2010
EMSA Registry
• 436 consecutive patients recruited
• Mean age at disease onset: 57.8 years
• Baseline disease duration: 5.8 years
• 68.2% MSA-P
• Symptomatic autonomic failure in 99%
• Urinary incontinence in 83%
• Orthostatic dysregulation in 75%
• Parkinsonism in 87%
• Ataxia in 63%
Köllensperger et al., 2010
EMSA Registry
Pharmacological Treatment
• Autonomic failure
• Orthostatic symptoms treated in 27%
• Midodrine – 69%
• Fludrocortisone – 25%
• Urinary dysfunction treated in 19%
• Tolterodine – 52%
• Oxybutinin – 45%
• Parkinsonism
• L-Dopa – 73% (beneficial response in 38%)
• DA – 29%
• MAO-B inihbitors – 11%
Köllensperger et al., 2010
Under-Treatment
Trial considerations
• Progression of motor impairment
• Progression of non-motor impairment
• Progression of global disability
• Worsening of Hr-QoL
• Progression of surrogate markers
UPDRS III progression
in MSA-P
H&Y
Male : female
Age (yrs)
Age at
symptom onset (yrs)
Disease duration
at baseline (yrs)
Follow-up duration
(months)
Annual UPDRS-III increase in PD:
1.5% ranging from 0.6-4.5
Olanow 1995; Louis 1999;
Goetz 2000; Jankovic 2001
13 : 21
64.0 ± 7.1
59.9 ± 6.6
4.1 ± 3.1
11.8 ± 1.4
Mean UPDRS-III change: 10.8 (95%CI 8.5 – 13.1)
H&Y 3 (n=22): 13.1 (95%CI 10.9 – 15.3)
H&Y  4 (n=12): 6.5 (95%CI 2.1 – 10.9)
Seppi K et al, 2005
EMSA – Natural History
Baseline
• Minimal Data
Set
• Rating Scales
(UMSARS, H&Y,
S&E, EQ5D, ...)
• Red Flag Screen
Wenning et al. 2013
6-Months
• Minimal Data
Set
• Rating Scales
(UMSARS, H&Y,
S&E, EQ5D, ...)
• Red Flag Screen
12-Months
• Minimal Data
Set
• Rating Scales
(UMSARS, H&Y,
S&E, EQ5D, ...)
• Red Flag Screen
18-Months
• Minimal Data
Set
• Rating Scales
(UMSARS, H&Y,
S&E, EQ5D, ...)
• Red Flag Screen
24-Months
• Minimal Data
Set
• Rating Scales
(UMSARS, H&Y,
S&E, EQ5D, ...)
• Red Flag Screen
EMSA - Natural History
N
Diagnostic certainty
Possible (%)
Probable (%)
Sex
Female (%)
Male (%)
Age
Study entry (years, mean ± SD)
Disease-onset (years, mean ± SD)
Disease duration baseline (years, mean ± SD)
Global disability scale (mean ± SD)
Schwab & England ADL (mean ± SD)
Hoehn & Yahr Parkinson (mean ± SD)
Symptomatic autonomic dysfunction (%)
Parkinsonism (%)
Beneficial L-Dopa Response(%)
Response duration (years, mean ± SD)
Ataxia (%)
Wenning et al., 2013
141
19.9
77.3
44.0
56.0
62.1 ± 7.7
56.2 ± 8.4
5.5 ± 3.8
2.3 ± 0.7
4.9 ± 2.2
3.7 ± 1.0
96.5
90.8
31.2
3.5 ± 2.7
71.6
EMSA – Natural History
Wenning et al., 2013
EMSA – Natural History
UMSARS Progression
60%
50%
40%
30%
20%
10%
0%
6-Months
Per Protocol Analysis
Wenning et al., 2013
12-Months
ADL
18-Months
ME
24-Months
Clinical Milestones
EMSA supported sample size
calculation for trials
30% effect size
30% effect size
 159 patients per group (80% power)
 186 patients per group (80% power)
Wenning et al., 2013
Factors associated with rapid progression
of motor impairment in MSA
• Lower baseline impairment
Seppi et al, 2005
• Absent L-Dopa response
Wenning et al, 2013
• Short disease duration
Seppi et al, 2005; Geser et al, 2006; Wenning et al, 2013
• Cerebellar features at baseline
Geser et al, 2006
Trial considerations
• Progression of motor impairment
• Progression of non-motor impairment
• Progression of global disability
• Worsening of Hr-QoL
• Progression of surrogate markers
Progression of self perceived
dysautonomia in MSA
6 months
Trial considerations
• Progression of motor impairment
• Progression of non-motor impairment
• Progression of global disability
• Worsening of Hr-QoL
• Progression of surrogate markers
H&Y progression in pathologically confirmed
parkinsonian disordes
H&Y progression
H&Y stages within 1 year of motor onset
100
H&Y I
H&Y II
Cases
Cases (%)
(%)
80
PD
H&Y III
60
MSA
DLB
PSP
HY I
HY II
40
HY III
20
0
PD
PD
CBD
CBD
DLB
DLB
Diagnosis
MSA
MSA
PSP
PSP
N=
18;
13;
11;
15;
24
N = 81
Median H&Y III latency in MSA: 43 months (6 – 100)
Median H&Y IV latency in MSA: 56 months (6 - 118)
Mueller et al., 2000
PROGRESSION IN MSA
Disability-milestones
MEDIAN TIME TO
years
Walking aids
3–5
Wheelchair
5–6
Bedridden state
Death
8
9.0 – 9.5
 approx. 50-60% of patients wheelchair-bound at 5 years
 Survival rate at 5 years approx. 84%
 Survival rate at 10 years approx. 40%
Wenning et al. 1994, N=100; Watanabe et al. 2002, N=230
Trial considerations
• Progression of motor impairment
• Progression of non-motor impairment
• Progression of global disability
• Worsening of Hr-QoL
• Progression of surrogate markers
Health-related Quality of Life in MSA
(Schrag et al, 2006)
- N = 115 pts. from EMSA-SG NH Study
- Impairment in all EQ-5D and SF-36 domains
- Significant impairments also relative to PD ! (except pain)
- Autonomic dysfunction (COMPASS), motor impairment
(UMSARS) and depression (BDI) closely associated with
poor Hr-QoL
- CAVE:
No change in SF-36, scores in sample of 27 MSA pts. from
4 EMSA-SG centres over 6 mths (Köllensperger et al, 2006)
Trial considerations
• Progression of motor impairment
• Progression of non-motor impairment
• Progression of global disability
• Worsening of Hr-QoL
• Progression of surrogate markers
SURROGATE ENDPOINTS IN MSA
Considerations
• Dopamine D2R
 DA-D2R-Imaging
(IBZM-SPECT,
Raclopride-PET)
• Striatal glucose metabolism  FDG-PET
• Dopamine transporter
 DAT-SPECT
(beta-CIT, FP-CIT)
• Striatal LD metabolism
 F-DOPA-PET
• Activated microglia
 PK11195-PET
• Basal ganglia atrophy
 MRT, MRV
• Putaminal diffusivity
 DWI (ADCs)
• CSF/Plasma Biomarkers
Completed Interventional Trials
rhGH Trial: Negative
- trophic factor support -
Holmberg et al. 2007, Aberg et al. 2000
Study design:
Double-blind RCT
Primary outcome:
UPDRS (52 weeks)
N
43
Phase:
Phase 2
PI:
B. Holmberg
Current Status:
Published
Study identifier:
Not registered
Minocycline (MEMSA): Negative
- microglial de-activation CD11b + Cresylviolet
PK11195-PET
Stefanova et al. 2007, Dodel et al. 2010
Study design:
Double-blind RCT
Primary outcome:
UMSARS II (48 weeks)
N
63
Phase:
Phase 3
PI:
W. H. Oertel
Current Status:
Published
Study identifier:
NCT00146809
Riluzole (NNIPPS): Negative
- anti-glutamatergic efficacy -
Scherfler et al. 2005, Diguet et al. 2005, Bensimon et al., 2009
Study design:
Double-blind RCT
Primary outcome:
Survival
N
398
Phase:
Phase 3
PI:
P. N. Leigh
Current Status:
Published
Study identifier:
NCT00211224
Rasagiline: Negative
- neuronal protection Apoptosis
Opening of MPTP pore
-
Caspase activation
MSA
MSA+R 2.5
Cytochrome c release
MSA
MSA+R 2.5
Stefanova et al. 2008, Poewe et al. 2012 (Poster 1182)
Study design:
Double-blind RCT
Primary outcome:
∆ UMSARS (48 weeks)
N
174
Phase:
Phase 2
PI:
W. Poewe
Current Status:
Completed
Study identifier:
NCT00977665
Mesenchymal Stem Cells
- cell replacement -
Lee et al 2012
Study design:
Double-blind RCT
Primary outcome:
UMSARS (52 weeks)
N
27
Phase:
Phase 2
PI:
P. H Lee
Current Status:
Published
Study identifier:
NCT00911365
Intravenous immunoglobulins
- Immunomodulation -
Study design:
Open label
Primary outcome:
Safety
N
9
Phase:
Phase 2
PI:
P. Novak
Current Status:
Published
Study identifier:
NCT00750867
Ongoing Interventional Trials
Rifampicin
- α-synuclein clearance -
Ubhi et al. 2008
Study design:
Double-blind RCT
Primary outcome:
∆ UMSARS (52 weeks)
N
100
Phase:
Phase 3
PI:
P. Low, S. Gilman, D.
Robertson
Current Status:
Data analysis
Study identifier:
NCT01287221
Fluoxetine
- trophic factor restoration -
Ubhi et al. 2012
Study design:
Double-blind RCT
Primary
outcome:
∆ UMSARS (52 weeks)
N
87
Phase:
Phase 2
PI:
O. Rascol
Current Status:
Data analysis
Study identifier:
NCT01146548
Future MSA Trials
Targets
•
•
•
•
Toxic alpha Synuclein species („prion-like“)
Oligodendroglia versus neurons
Oxidative stress (CoQ 2 mutations)
Neuroinflammation
Future MSA Trials
Design
•
•
•
•
Placebo-controlled vs open label
Parallel group vs cross over
Large versus small
Other?
Future MSA Trials
Population
•
•
•
•
•
MSA-P
MSA-C
MSA-AF (OH, UGF, both)
Early, mid-stage
Large size (>200)
Future MSA Trials
Endpoints
•
•
•
•
•
Motor
Autonomic
Cognitive
Psychiatric
QoL/pharmacoeconomics
Future MSA Trials
Logistics
• Funds
• Academic networks
• Registries
EU (7FP/Horizon 2020), NIH
EMSA, US-ADRC, JAMSA
EMSA-R, GLOMSAR
Important: Support by national MSA groups incl. UK
MSA Trust, Belgian/Dutch/French/German MSA
Societies, US MSA Coalition, US MSA Awareness, US
Fight MSA Initiative
Division of Neurobiology
Department of Neurology
Medical University Innsbruck