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SYMPTOM MANAGEMENT: PHARMACOLOGIC THERAPY Christopher T. Bever, Jr., M.D. Director, MS CoE - East June 5, 2004. Progressive. Preclinical. Relapsing. Symptoms in Progressive MS. Time. Hartung HP et al. The Lancet. 2002;360:2018-2025. Symptoms of MS. Ataxia and tremor - PowerPoint PPT Presentation
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CMSC, June 2004
SYMPTOM MANAGEMENT:SYMPTOM MANAGEMENT:
PHARMACOLOGICPHARMACOLOGIC
THERAPYTHERAPY
Christopher T. Bever, Jr., M.D.Christopher T. Bever, Jr., M.D.
Director, MS CoE - EastDirector, MS CoE - East
June 5, 2004June 5, 2004
CMSC, June 2004
Symptoms in Progressive MS
RelapsingRelapsingPreclinicalPreclinical ProgressiveProgressive
Hartung HP et al. Hartung HP et al. The Lancet.The Lancet. 2002;360:2018-2025. 2002;360:2018-2025.
TimeTime
CMSC, June 2004
Symptoms of MS Ataxia and tremorAtaxia and tremor Bladder and bowel dysfunctionBladder and bowel dysfunction Cognitive ImpairmentCognitive Impairment DepressionDepression FatigueFatigue PainPain Sexual dysfunctionSexual dysfunction Spasticity and weaknessSpasticity and weakness Visual disturbancesVisual disturbances
IOM Report, 2001
CMSC, June 2004
Symptom Classifications
Primary vs. secondary vs. tertiaryPrimary vs. secondary vs. tertiary Neurological vs. non-neurologicalNeurological vs. non-neurological Negative vs. positiveNegative vs. positive Fixed vs. paroxysmalFixed vs. paroxysmal
A. Miller, 2000
CMSC, June 2004
Treatable Symptoms of MS
Ataxia and tremorAtaxia and tremor Bladder and bowel dysfunctionBladder and bowel dysfunction Cognitive impairmentCognitive impairment DepressionDepression FatigueFatigue Paroxysmal symptomsParoxysmal symptoms Sexual dysfunctionSexual dysfunction SpasticitySpasticity WeaknessWeakness
CMSC, June 2004
Treatable Symptoms of MS
Ataxia and tremorAtaxia and tremor Bladder and bowel dysfunctionBladder and bowel dysfunction Cognitive impairmentCognitive impairment DepressionDepression FatigueFatigue Paroxysmal symptomsParoxysmal symptoms Sexual dysfunctionSexual dysfunction SpasticitySpasticity WeaknessWeakness
CMSC, June 2004
Treatable Symptoms of MS
Ataxia and tremorAtaxia and tremor Bladder and bowel dysfunctionBladder and bowel dysfunction Cognitive impairmentCognitive impairment DepressionDepression FatigueFatigue Paroxysmal symptomsParoxysmal symptoms Sexual dysfunctionSexual dysfunction SpasticitySpasticity WeaknessWeakness
CMSC, June 2004
Fatigue in MS
Subjective lack of physical or Subjective lack of physical or mental energy to carry out usual mental energy to carry out usual activitiesactivities
Present at some time in 75%-90% Present at some time in 75%-90% of patients with MSof patients with MS
Present daily in 46%-66% Present daily in 46%-66%
CMSC, June 2004
Fatigue: Proposed Treatments AmantadineAmantadine PemolinePemoline SSRI’sSSRI’s AmphetaminesAmphetamines AminopyridinesAminopyridines ModafanilModafanil Behavior modificationBehavior modification
CMSC, June 2004
Amantadine
Developed as an anti-viral agentDeveloped as an anti-viral agent Identified by a chance observation Identified by a chance observation
as improving MS fatigueas improving MS fatigue Class I evidence from four trials Class I evidence from four trials
supports its use in MS patientssupports its use in MS patients Response rates of 20% to 40% at Response rates of 20% to 40% at
100 mg bid100 mg bid
CMSC, June 2004
Modafanil
Novel wakefulness-promoting agentNovel wakefulness-promoting agent Mechanism of action unknownMechanism of action unknown Low abuse potential (Schedule IV)Low abuse potential (Schedule IV) FDA approval for narcolepsyFDA approval for narcolepsy
CMSC, June 2004
Phase II Trial in MS
Randomized, patient-blind, placebo-Randomized, patient-blind, placebo-controlled crossover design phase II trialcontrolled crossover design phase II trial
72 patients enrolled at two sites72 patients enrolled at two sites Outcome measures:Outcome measures:
FSS (primary)FSS (primary) MFISMFIS VAS-FVAS-F Epworth sleepiness scaleEpworth sleepiness scale
CMSC, June 2004
Results: FSS
4.2
4.4
4.6
4.8
5
5.2
5.4
5.6
Placeborun in
Modafanil200mg
Modafanil400mg
Placebowashout
FSS
*p<0.001, Placebo run in vs Modafanil 200mg
*
CMSC, June 2004
Results: MFIS
3.4
3.6
3.8
4
4.2
4.4
4.6
Placeborun in
Modafanil200mg
Modafanil400mg
Placebowashout
MFIS
*p<0.001, Placebo run in vs Modafanil 200mg
*
CMSC, June 2004
Results: VAS-F
0
1
2
3
4
5
6
Placeborun in
Modafanil200mg
Modafanil400mg
Placebowashout
VAS-F
*p<0.003, Placebo run in vs Modafanil 200mg
*
CMSC, June 2004
Adverse Events
< 10% of patients< 10% of patients More common during treatment:More common during treatment:
NauseaNausea Anxiety, nervousnessAnxiety, nervousness Dry mouthDry mouth InsomniaInsomnia DiarrheaDiarrhea AstheniaAsthenia
CMSC, June 2004
Conclusions
Fatigue is one of the most common Fatigue is one of the most common symptoms in MS patientssymptoms in MS patients
Pharmacological treatments are an Pharmacological treatments are an important part of fatigue managementimportant part of fatigue management
Amantadine is effective, cheap and Amantadine is effective, cheap and well toleratedwell tolerated
Modafanil is effective and well Modafanil is effective and well toleratedtolerated
CMSC, June 2004
Treatable Symptoms of MS
Ataxia and tremorAtaxia and tremor Bladder and bowel dysfunctionBladder and bowel dysfunction Cognitive impairmentCognitive impairment DepressionDepression FatigueFatigue Paroxysmal symptomsParoxysmal symptoms Sexual dysfunctionSexual dysfunction SpasticitySpasticity WeaknessWeakness
CMSC, June 2004
Weakness
One of the most common and One of the most common and disabling symptoms in MSdisabling symptoms in MS
Usually due to upper motor neuron Usually due to upper motor neuron dysfunctiondysfunction
Loss of voluntary control Loss of voluntary control exacerbated by de-conditioningexacerbated by de-conditioning
Primary therapy is exercisePrimary therapy is exercise
CMSC, June 2004
Aminopyridine Potassium Channel Blockers Nonspecific blockers of voltage Nonspecific blockers of voltage
sensitive potassium channelssensitive potassium channels Improve action potential Improve action potential
propagation in demyelinated axonspropagation in demyelinated axons Increase transmitter release at Increase transmitter release at
synaptic endingssynaptic endings
CMSC, June 2004
3,4 Diaminopyridine
Orally activeOrally active Short serum half-lifeShort serum half-life Crosses blood brain barrier poorlyCrosses blood brain barrier poorly Available for the treatment of Available for the treatment of
Lambert-Eaton Myasthenic Lambert-Eaton Myasthenic SyndromeSyndrome
CMSC, June 2004
Phase II Trial of DAP in MS Double-blind, placebo-controlled, Double-blind, placebo-controlled,
crossover trialcrossover trial 22 MS patients with leg weakness22 MS patients with leg weakness One month treatment periods with up to One month treatment periods with up to
100 mg per day100 mg per day Outcome measures:Outcome measures:
Patient and physician impressions of Patient and physician impressions of changechange
Manual motor testingManual motor testing Quantitative motor testingQuantitative motor testing Ambulation indexAmbulation index
CMSC, June 2004
Results: # Improved
OutcomeOutcome DAPDAP PlaceboPlacebo pp
Physician IC Physician IC 2121 11 0.0050.005Patient ICPatient IC 1414 22 0.0080.008MMTMMT 1616 33 0.0020.002QMT-HSQMT-HS 1616 99 0.0010.001QMT-QQMT-Q 1515 88 0.040.04AIAI 55 00 0.020.02
CMSC, June 2004
Results: Mean scores
OutcomeOutcome DAPDAP PlaceboPlacebo pp
MMTMMT 41.641.6 39.939.9 0.0020.002QMTQMT -HS-HS 130130 123123 0.0010.001QMT-QQMT-Q 231231 206206 0.040.04
CMSC, June 2004
Results: Mean Strength Scores
30
32
34
36
38
40
42
44
0 4 8 12 16
Week
Mean M
MT s
core
Placebo-DAPDAP-Placebo
CMSC, June 2004
Results: Mean AI Scores
3.8
4.8
5.8
6.8
0 4 8 12 16Week
Mean A
I sc
ore
Placebo-DAPDAP-Placebo
CMSC, June 2004
Conclusions
3,4 DAP treatment can improve leg 3,4 DAP treatment can improve leg strength in selected patientsstrength in selected patients
3,4 DAP treatment can improve 3,4 DAP treatment can improve ambulation times in a subset of ambulation times in a subset of patientspatients
3,4 DAP treatment causes 3,4 DAP treatment causes paresthesias and gastrointestinal paresthesias and gastrointestinal adverse events that limit its useadverse events that limit its use
Rarely 3,4 DAP treatment can cause Rarely 3,4 DAP treatment can cause seizuresseizures
CMSC, June 2004
4-Aminopyridine
Orally activeOrally active Crosses blood brain barrier readilyCrosses blood brain barrier readily Longer half-life than DAPLonger half-life than DAP Used to reverse neuromuscular Used to reverse neuromuscular
blockade after surgeryblockade after surgery
CMSC, June 2004
Trials of 4-Aminopyridine in MS Jones et al: Open label pilotJones et al: Open label pilot Davis & Stefoski: Controlled crossoverDavis & Stefoski: Controlled crossover Van Diemen, et al: Randomized, Van Diemen, et al: Randomized,
controlled, crossovercontrolled, crossover Bever et al: Randomized, controlled, Bever et al: Randomized, controlled,
crossovercrossover Schwid et al: Randomized, controlled, Schwid et al: Randomized, controlled,
crossovercrossover Goodman et al: Randomized, DB, PC Goodman et al: Randomized, DB, PC
parallel groupparallel group
CMSC, June 2004
Objectives Primary: Determine safety of multiple doses of Primary: Determine safety of multiple doses of
fampridine-SR (one week each of 20 mg/day, 30 fampridine-SR (one week each of 20 mg/day, 30
mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70
mg/day and 80 mg/day).mg/day and 80 mg/day).
Secondary: Obtain evidence of efficacy and dose-Secondary: Obtain evidence of efficacy and dose-
response using several outcome measuresresponse using several outcome measures Standard MS measurements, including timed walk, Standard MS measurements, including timed walk,
lower extremity muscle strength, PASAT, 9-hole peg lower extremity muscle strength, PASAT, 9-hole peg
testtest Daily Fatigue Diary – Brief Fatigue InventoryDaily Fatigue Diary – Brief Fatigue Inventory
Goodman, A, 2002
CMSC, June 2004
CMSC, June 2004
Dose Response- 25 ft Walk
10
11
12
13
14
15
16
17
18
scre
en
base
1
base
2
base
3ru
n-in
20m
g30
mg
40m
g50
mg
60m
g70
mg
80m
g
Tim
e (s
ecs)
All subjects (n=25)
Completers (n=20)
CMSC, June 2004
Leg strength
-20 0 20 40 60 80
1
4
7
10
13
16
19
22
25
Change in LEMMT (%)
-20 0 20 40 60 80
1
3
5
7
9
11
Change in LEMMT (%)
Fampridine-SR(20-50 mg/day)
Placebo
BetterWorse
CMSC, June 2004
Treatment emergent adverse events Fampridine-SR
(N=25)Placebo(N=11)
No. with AEs All AEs 25 (100%) 10 (90.9%) Most Frequently Reported AEs Dizziness 9 (36.0%) 2 (19.2%)Insomnia 9 (36.0%) 1 (9.1%)Paresthesia 8 (32.0%) 1 (9.1%)Nausea 7 (28.0%) 1 (9.1%)Asthenia 7 (28.0%) 1 (9.1%)Headache 6 (24.0%) 1 (9.1%)Tremor 6 (24.0%) 0Pain 5 (20.0%) 0Back Pain 5 (20.0%) 0Anxiety 3 (12.0%) 0Hypertonia 1 (4.0%) 3 (27.3%)
CMSC, June 2004
Safety Summary The most common adverse events in the The most common adverse events in the
fampridine treated group were consistent fampridine treated group were consistent with the findings of previous studieswith the findings of previous studies Dizziness, Insomnia, Parasthesia, Nausea, Asthenia, Dizziness, Insomnia, Parasthesia, Nausea, Asthenia,
Headache, TremorHeadache, Tremor
At doses above 40 mg/day, more severe At doses above 40 mg/day, more severe adverse events were reported, including adverse events were reported, including two cases of seizure (at 60 and 70 two cases of seizure (at 60 and 70 mg/day)mg/day)
As anticipated, the risk of seizure requires As anticipated, the risk of seizure requires further study and characterization further study and characterization particularly in the anticipated dose rangeparticularly in the anticipated dose range
CMSC, June 2004
Summary Safety profile consistent with previous experienceSafety profile consistent with previous experience
Significant* benefit on timed walking (p=0.04)Significant* benefit on timed walking (p=0.04)
Significant* benefit on lower extremity strength Significant* benefit on lower extremity strength
(p=0.01)(p=0.01)
Evidence of dose-response in 20-40 mg/day rangeEvidence of dose-response in 20-40 mg/day range
No evidence of benefit on overall fatigue No evidence of benefit on overall fatigue
Little added benefit, and increased AEs at doses Little added benefit, and increased AEs at doses
above 50 mg/dayabove 50 mg/day
*repeated measure ANOVA (weeks 1-7)