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Early Diagnosis and Intervention In Parkinson

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Title: Early Diagnosis and Intervention In Parkinson


1
Early Diagnosis and Intervention In Parkinsons
Disease Can We Affect Clinical Outcomes with
Early Therapy What the Evidence Tells Us
The Science and Medicine of Parkinsons
Disease
  • Mark F. Lew, MD
  • Professor Of Neurology
  • Director Division Of Movement Disorders
  • Vice-chair Department Of Neurology
  • Keck/USC School Of Medicine
  • Los Angeles, California

2
Parkinsons Disease Old News
  • Chronic progressive neurodegenerative disorder
  • Characterized by loss of dopaminergic neurons in
    the substantia nigra
  • Clinical features of Parkinsons Disease
  • Tremor, rigidity and bradykinesia
  • Postural instability in later stages
  • Autonomic failure (constipation, orthostasis,
    impotence)
  • Neuropsychiatric dysfunction (depression,
    dementia)

Playfer. Postgrad Med. 199773257-264 Olanow Et
Al. Neurology. 200156 (Suppl 5)s1-s88 Barbosa
Et Al. Psychiatr Clin North Am. 199720769-790
.Bhatia Et Al. Hosp Med. 199859469-480.
3
Parkinsons Disease Epidemiology
  • Approximately 1 million patients in US
  • 40,000 to 60,000 new cases/year
  • Average age of onset is 60 years, predominantly
    males
  • Affects up to 0.3 of general population
  • 1 to 3 of those older than 65 years
  • Prevalence increasing as the population ages

Rajput Et Al. Ann Neurol. 198416278-282.
Barbosa Et Al. Psychiatr Clin North Am.
199720769-790. Olanow Et Al. Neurology.
200156 (11 Suppl 5)s1-s88.Schrag Et Al. Bmj.
200032121-22.
4
When to Start Therapy?
  • Wait until patient is simply bothered by
    symptoms?
  • Wait until patient has functional disability?
  • Wait until patient really needs treatment?
  • As soon as a diagnosis is made?

5
Is the Gold Standard Really Golden?
  • Levodopa/carbidopa Dopamine precursor
  • Most effective therapy Gold standard?
  • Early side effects Nausea and hypotension
  • Long term side effects Dyskinesias and motor
    fluctuations such as wearing off

Olanow et al. Neurology. 200156 (suppl
5)S1-S88. Jankovic and Tolosa. Parkinsons
Disease and Movement Disorders. 3rd ed.
Philadelphia Lippincott Williams Wilkins
1998177-190. Sinemet (carbidopa-levodopa).
Complete prescribing information. Merck Co.
Inc. Bristol-Myers Squibb Co. April
2002. Barbosa et al. Psychiatr Clin North Am.
199720769-790.
6
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7
Landmark Trials in Parkinsons Disease
2004351 (Dec 9)2498-2508
8
Goal and Purpose of Trial
  • To determine if levodopa alters the natural
    history of PD. Does it hasten it, slow it down,
    or does it have no effect?
  • Corollary Should levodopa be started earlier or
    later in the natural history of this disease?

9
THE ELLDOPA STUDY CHANGE IN TOTAL UPDRS FROM
BASELINE
Placebo
150mg
300mg
600mg
Medications withdrawn
Baseline
NEJM 2004351 (Dec 9)2498-2508
10
Dopaminergic AES ELLDOPA Trial
Placebo 150mg/d 300mg/d 600mg/d p-Value
ENROLLED 90 92 88 91
Any 33 / 37 33 / 36 27 / 31 37 / 41 0.5177
Wearing-off 12 / 13 15 / 16 16 / 18 27 / 30 0.0596
Dyskinesia 3 / 3 3 / 3 2 / 2 15 / 16 0.0001
On-off 3 / 3 1 / 1 0 / 0 3 / 3 0.2602
Dystonia 19 / 21 19 / 21 14 / 16 12 / 13 0.3001
Freezing 13 / 14 9 / 10 6 / 7 5 / 5 0.1497
N / Percent
NEJM 2004351 (Dec 9)2498-2508
11
Dopamine Agonists vs. Levodopa
100
Levodopa (n150)
100
Levodopa (n89)
Pramipexole (n151)
74
80
Ropinirole (n179)
80
()
()
63
54
52
60
60
47
45
34
40
40
25
23
20
20
20
0
0
1st Complication
Wearing off
Dyskinesia
Wearing off
Dyskinesia
Rascol et al. N Engl J Med 20003421484-1491
Parkinson Study Group. Arch Neurol 2004
611044-1053.
Courtesy K. Lyons, PhD. 2006
12
Side Effects of Dopamine Agonists vs. Levodopa
Levodopa Ropinirole Levodopa Pramipexole
Somnolence 19 27 21.3 36.4
Peripheral edema 5.6 14 14.7 42.4
Hallucinations 5.6 17 8 14.6
Nausea 49 49 38 38.4
Postural hypotension 12 12 15 9



Rascol O et al. (2000), N Engl J Med
342(20)1484-1491 Parkinson Study Group (2000),
JAMA 284(15)1931-1938 PSG (2004), Arch Neurol
61(7)1044-1053
13
Old School Thinking
14
Does Early Diagnosis Early Treatment?
Initiating Treatment for Parkinsons Disease
  • If we had a therapy that was shown to be . . .
  • 1) Efficacious compared to placebo
  • 2) Safe and well tolerated
  • 3) Potentially disease modifying
  • This would compelling argument that everyone
    with PD should take this medication as soon as
    they were diagnosed without delay.

15
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16
TEMPO Delayed-Start Design
Randomization
Rasagiline 1 mg/day
Rasagiline 1mg/day
N124
N134
Rasagiline 2 mg/day Rasagiline
2mg/day
N124
N132
Placebo
Delayed Rasagiline 2 mg/day
X
N404
N132
N138 At 6 months in Delayed Start
Placebo group receives 2mg
Double-Blind Active Treatment Phase
Double-Blind Placebo-Controlled Phase
6 Months
6 Months
  • Parkinson Study Group. Arch Neurol. 2004
    61561-566.

Parkinson Study Group. Arch Neurol 2002
591937-43.
17
Baseline Demographics and Clinical
Characteristics
Parameter Patients ever Treated with Rasagiline in TEMPO (N 398)
Age, y SD 60.9 10.8
Caucasian, n () 377 (94.7)
Male, n () 253 (63.6)
PD duration, years SD 1.2 1.2
Total UPDRS, mean SD 26.1 11.5
Hoehn Yahr stage SD 1.9 0.5
Parkinson Study Group. Arch Neurol. 2002
591937-43.
18
TEMPO Primary Efficacy Measure Treatment Effect
on Total UPDRS at 6 Months
(Primary Analysis Adjusted Mean SE)
Mean Change from baseline in Total UPDRS
4.07
Rasagiline 1 mg
Rasagiline 2 mg
Placebo
0.51
-0.13
P lt 0.0001
P lt 0.0001
Parkinson Study Group. Arch Neurol. 2002
591937-43.
19
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20
Symptomatic versus Disease-Modifying Effects
Delayed-start
Delayed-start catches up
Symptom improvement
Time
Delayed-start
Delayed-start does not catch up
Symptom improvement
Time
Design contributed by R. Hauser
21
TEMPO Adverse Event Frequency Similar To Placebo
Infection
Headache
Accidental Injury
Dizziness
Asthenia
Nausea
Rasagiline 1mg
Arthralgia
Rasagiline 2mg
Back Pain
Placebo
of patients reporting
Pain
0
2
4
6
10
14
16
18
8
12
Parkinson Study Group. Arch Neurol. 2002
591937-43.
22
TEMPO Study Conclusions
  • In early PD patients
  • Rasagiline effectively manages symptoms over 1
    year
  • Frequency of AEs similar to placebo
  • Results from delayed start design suggests
  • Effects of rasagiline on the progression of
    disability in patients with PD cannot be fully
    explained by its symptomatic effect and may be
    due to disease modifying activity of the drug.

Parkinson Study Group. Arch Neurol. 2004
61561-566
23
Old School Revisited
24
TEMPO Long Term, Open Label Follow
Up
To examine the effect of early- versus
delayed-start rasagiline on long-term PD symptom
progression
Some patients have been followed for up to
8.5 years
Lew Et Al Submitted For Publication European
Journal Of Neurology
25
TEMPO 2 Years Monotherapy
M. Lew Presented 9/2005 EFNS
26
Change From Baseline Total UPDRS Long-term
Rasagiline Therapy Without Dopaminergics
M. Lew Presented 9/2005 EFNS
27
Percent Change From Baseline UPDRS For Early
versus Delayed Rasagiline
M.Lew Presented EFNS 9/2005
28
Conclusions Early Treatment
  • Early versus delayed rasagiline therapy is
    associated with less PD symptom progression at 1
    year1
  • Current long-term analysis shows this advantage
    persists in patients treated for up to 6 years2
  • Treating early with rasagiline is beneficial for
    PD patients

1Parkinson Study Group. Arch Neurol.
200461561-566 2Lew
EFNS 2005
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