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

• 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

• 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

10

12

14

16

18

20

22

Diagnostic Confidence

Volume cubic cm

0 321

Depression (BDI) and Diagnostic Confidence

0

2

4

6

8

10

Diagnostic Confidence

BDI Score

C 1 2 30

* * * *

* = 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 dementiahttp://www.clinicaltrials.gov/ct/show/NCT00294554?order=25

• 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)

IncreaseDecrease

A fMRI research study to learn more about multiple sclerosis and individuals potentially

experiencing memory difficultieshttp://www.clinicaltrials.gov/ct/show/NCT00315367?order=17

• 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 sclerosishttp://www.clinicaltrials.gov/ct/show/NCT00134563?order=32

• 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

http://www.pharmacorama.com/Rubriques/Output/Synthese_DNA_RNAa3_5.php

leflunomide

teriflunomide

• 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

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Steinman and Zamvil, Ann. Neurol., 2006

Likely Outcome:

Continue?

Cons:

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Reproductive HepaticLong term efficacy

Oral treatmentActive lesion reductionCombinatorial

Pros:

Sensory cues for freezing in Parkinson’s disease

http://www.clinicaltrials.gov/ct/show/NCT00322426?order=1

• 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).

• 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.

20 Subjects with PD

Outcome Measures:Walking Time & Freezing Time in 15m Strip

Number of Freezes

Average Duration of Freeze

No Cue

Sensory

Cueing

Device

Auditory

Visual

Tactile

Random

Sensory Cues for Freezing in Parkinson’s Disease Clinical Trial

A randomised controlled trial of neuroprotection with lamotrigine in secondary progressive

multiple sclerosishttp://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)