NOD 2007 presents
clinical trials on review
starring a cast of 27
Safety and efficacy of motor cortex stimulation
in Parkinson’s disease
http://www.clinicaltrials.gov/ct/show/NCT00159172?order=3a
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Tara Phillips
Zev Einhorn
Katherine Saylor
Karin Mullendorf
Any Bruestle
Phase I study of motor cortex
stimulation in the treatment of PD
• MCS disrupts abnormal
neural activity
• Reversible, unlike
lesioning
• Reduced drug
dependence
• Less invasive than DBS
• Longer duration than
repetitive TMS
www.drugstop.com
Anticipated Outcomes
• Mixed outcomes in human
studies
• Ameliorated bradykinesia
and akinesia in MPTP
primates
• Disadvantageous clinical
latency (mins-days)
• Phase I should continue
– Safe, so far
– Increased eligibility pool for
stimulation surgery
Drouot X et al. 2004
Neurobiological predictors of Huntington’s
Disease (PREDICT-HD)
http://www.clinicaltrials.gov/ct/show/NCT00051324?order=1
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Lindsey Leigland
Skyla Herod
David Roalf
Rachel Sanchez
Huntington’s Disease & the PREDICT-HD Study
• HD is an incurable, inherited AD disease
• PREDICT-HD is an multisite, observational, longitudinal study of
907 individuals allelic positive for the CAG expansion mutation
in the HD gene.
• PREDICT-HD is designed to provide cognitive, psychiatric,
motor, and neuroanatomical information about the CAG +
individuals
• Early Intervention model for adult-onset disease
Green arrow indicates administration of an effective prophylactic neuroprotective agent in a treated individual.
Red arrow represents clinical diagnosis of an untreated individual. Taken from Paulsen et al., 2006
Diagnostic Confidence and Striatum Volume
Depression (BDI) and Diagnostic Confidence
10
20
18
16
14
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*
1
2
3
6
4
2
12
10
*
8
BDI Score
Volume cubic cm
22
0
1
2
3
0
C
Diagnostic Confidence
0
Diagnostic Confidence
*
= significantly different from controls
Benefits and Likely Outcomes:
1) Determination of biomarkers
2) Targeted outcome measures for future clinical trials
3) Provide estimate of disease onset
4) Multiple points of treatment
Herod, Leigland, Roalf, Sanchez
Memantine for treatment of cognitive
impairment in patients with Parkinson’s disease
and dementia
http://www.clinicaltrials.gov/ct/show/NCT00294554?order=25
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Pete Groblewski
Angela Scibelli
Kyle Ambert
Fred Franken
Memantine
•Voltage-dependent uncompetitive NMDA-r antagonist, moderate affinity
•Blocks glutamatergic overactivity by inhibiting
prolonged Ca++ influx
•FDA approved as a monotherapy in patients
with moderate Alzheimer’s disease, but is often
combined with cholinesterase inhibitors for
treatment of more severe cases
Presenters: Kyle Ambert, Fred Franken, Pete Groblewski, Angela Scibelli
Memantine for Treatment of Cognitive Impairment in Patients
with Parkinson’s Disease and Dementia
PURPOSE: To assess the effects of memantine on the cognitive impairment in
patients with idiopathic Parkinson’s disease and dementia
DESIGN: RDBPC (n=20, balanced for concomitant AchE-inhibitor)
DV: Cognitive Efficacy (memory tests, clinical global impression of change scores,
& Dementia Rating Scale (DRS))
DOSE: Memantine group: 5-20 mg/day (escalating/titrated dose)
Increase
Decrease
A fMRI research study to learn more about
multiple sclerosis and individuals potentially
experiencing memory difficulties
http://www.clinicaltrials.gov/ct/show/NCT00315367?order=17
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Clayton Winkler
Bob Cargill
Henry Li
Hongyu Zhao
An fMRI Research Study to Learn More About MS
and Individuals Experiencing Memory Difficulties
Design:
Interventional Treatment - Randomized, Double-Blind, Placebo Control Efficacy Study
Intent:
•Support previous studies showing memory improvement using Donepezil (Aricept®)
•Develop fMRI as a clinical tool to measure drug efficacy – “surrogate marker”
Basic Science Rationale:
•Cholinergic hypothesis: decreased ChAT in basal forebrain in AD
•MRI hyperintensity in ACh pathways in MS lesions correlated to memory loss
•Improvement in memory demonstrated in AD using ChE inhibitors
•PET, SPECT studies show increased cerebral blood flow in AD patients treated with cholinesterase
inhibitors (Matsuda, 2001) in frontal cortex (Kaasinen et al., 2002)
•Enhanced fMRI frontal activation in working memory task in AD (Rombouts et al., 2002)
•No controlled fMRI studies of treatment effects published in MCI or AD to date
•Effects of donepezil on memory and cognition in MS. (Christodoulou J Neurol Sci 2006)
Proposed Drug Mechanisms:
•Increases in AChR count in frontal region (Barnes et al. 2000)
•Replace lost ACh due to disruption of axonal transport (Krupp Neurology 2004)
•Hyperemia - neurovascular coupling induced by ACh levels (Blin Brain Res 1994)
Outcomes:
•Drug efficacy and fMRI correlation depends on lesion location
•Understanding of drug-dependent anatomic changes during cognition
•Refining clinical tool for quantification of patient drug efficacy and disease progression
Cost/Benefit Analysis:
•Opportunity cost – while “experimental group” receives low-risk approved treatment, placebo group
forgoes readily available treatment
•Benefits of fMRI minimal –
mostly for understanding drug
mechanism, future clinical utility
•Results in 2-3 years
•Trial worthwhile but alternative
targets are under examination
(eg. N-acetyl aspartate)
Study of teriflunomide in reducing the frequency
of relapses and accumulation of disability in
patients with multiple sclerosis
http://www.clinicaltrials.gov/ct/show/NCT00134563?order=32
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Stephen Magill
Mike Walogorsky
Rebecca Mongeon
Shin Draper
Study of Teriflunomide in Reducing the Frequency of Relapses and
Accumulation of Disability in Patients With Multiple Sclerosis
• Phase III, double-blind, placebo controlled, two year, interventional, randomized
• Requirements: 18-55 year old RRMS patients
• Measurements:
•Expanded Disability Status Scale (EDSS)
•Cerebral MRI every 24 weeks
leflunomide
teriflunomide
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Steinman and Zamvil, Ann. Neurol., 2006
http://www.pharmacorama.com/Rubriques/Output/Synthese_DNA_RNAa3_5.php
Likely Outcome:
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Cons:
Reproductive
Hepatic
Long term efficacy
Pros:
Oral treatment
Active lesion reduction
Combinatorial
Continue?
Sensory cues for freezing in Parkinson’s
disease
http://www.clinicaltrials.gov/ct/show/NCT00322426?order=1
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Jessica Siegel
James Stafford
Charlene Voorhees
Lauren Dobbs
Freezing of Gait in Parkinson’s
Disease
FOG is an extreme form of gait dysrhythmicity (patients feel that
their feet are “glued” to the floor).
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Prevalence of FOG ranges between 20 and 60% and is usually
associated with increased severity and duration of PD
FOG generally lasts between 10 and 30 seconds
With the progression of PD, FOG can become more frequent and
disabling
FOG has been treated with selegiline and L-dopa, but current research
is focusing on using visual cues, auditory cues, or rhythmic
somatosensory cueing to encourage better control of gait and greater
stride length.
No Cue
Sensory Cues for Freezing in
Parkinson’s Disease Clinical Trial
Auditory
20
Subjects
with PD
Sensory
Cueing
Visual
Device
Tactile
Random
Outcome Measures:
Walking Time & Freezing Time in 15m Strip
Number of Freezes
Average Duration of Freeze
A randomised controlled trial of neuroprotection
with lamotrigine in secondary progressive
multiple sclerosis
http://www.clinicaltrials.gov/ct/show//NCT00257855?order=6
• Laura Villasana
• Jeffrey Iliff
Axonal protection achieved in a model of multiple sclerosis using
lamotrigine
Bechtold, D.A, Miller S.J, Dawson, A.C, Sun, Y., Kapoor, R., Berry, D., Smith, K.
Lamotrigine for Secondary Progressive Multiple
Sclerosis: Study Details and Prospectus
Study Details
– Phase II (efficacy)
– Randomized, double-blind, placebo
control
Primary Outcomes
– Brain atrophy: change in brain
volume on MRI
Secondary Outcomes
– Change in lesion quality/quantity by
MRI
– Spinal cord atrophy
– Extended Disability Scaling Score
– Functional Composite
– Impact Scale
Time Course
– Two years
From Black et al. Brain (2006)