Evidence-based review of current
Parkinson’s disease treatments
This educational material has been supported by Abbott
Evidence-based review of current Parkinson’s
disease treatments
Duodenal carbidopa/levodopa gel
infusion treatment
<<Insert speaker’s name and affiliation here>>
Learning objectives
At the end of this section you will:
• Be aware of the current evidence base for duodenal
carbidopa/levodopa gel infusion treatment of advanced
Parkinson’s disease
• Gain greater knowledge of the clinical efficacy and tolerability
profile of duodenal carbidopa/levodopa gel infusion treatment
• Know the effectiveness of duodenal carbidopa/levodopa gel
infusion treatment for the alleviation of motor complications
when compared with standard pulsatile dopaminergic
treatments
Multiple versus continuous dosing of
duodenal carbidopa/levodopa gel infusion
Multiple dosing of levodopa is associated with increased
risk of motor complications
Obeso J, et al. Trends Neurosci 2000;23(suppl):S1-S19.
Multiple versus continuous dosing of
duodenal carbidopa/levodopa gel infusion
Continuous dosing of carbidopa/levodopa gel infusion
is associated with more normal motor functioning
Obeso J, et al. Trends Neurosci 2000;23(suppl):S1-S19.
Intestinal access
Endoscopic placement of PEG
Carbidopa/levodopa gel infusion therapy
• Levodopa/carbidopa (2 g/day) in
gel suspension
• 100 ml cassette (2000 mg)
• PEG with intestinal tube
• Ambulatory pump
• Morning bolus dose
• Continuous maintenance infusion
over 16 hr
Duodenal carbidopa/levodopa gel infusion:
Overview of clinical efficacy
Study
Change in motor state with duodenal
carbidopa/levodopa gel infusion
Nilsson et al, 1998
Functional
‘on’ time
+ 24
+ 26
Nilsson et al, 2001
+ 13
Nyholm et al, 2003
‘Off’
time
-5
- 23
Patients (N) Time
Dyskinesia
- 19
-4
7
2
6m
2.5 y
+ 7*
- 21
6
4–7 y
+ 19
- 13
-6
12
3w
Nyholm et al, 2005
+ 16
- 17
+2
24
3w
Antonini et al, 2007
+ 42
- 28
- 13
7
1y
Eggert et al, 2008
+ 51
- 39
- 12
13
12 m
Puente et al, 2010
+ 40
- 66
N/A
9
18 m
*Increase in ‘off’ mainly due to walking difficulties in one patient; if this patient is excluded, functional ‘on’
is + 22, ‘off’ is - 7, and dyskinesia is - 15 (N=5)
Nilsson D, et al. Acta Neurol Scand 1998;97:175-83. Nilsson D, et al Acta Neurol Scand 2001;104:343-8. Nyholm D, et al. Clin Neuropharmacol 2003;26:156-63.
Nyholm D, et al. Neurology 2005;64:216-23. Eggert K, et al, Clinical Neuropharm 2008;31:151-66. Antonini A, et al. Mov Disord 2007;22:1145-9. Antonini A, et al.
Neurodegenerative Dis. 2008;5:244-46. Puente V, et al. Parkinsonism Relat Disord 2010;16:218-21.
Duodenal carbidopa/levodopa gel infusion:
Overview of clinical efficacy, continued
Study
Change in motor state with duodenal
carbidopa/levodopa gel infusion
‘Off’
Dyskinesia
Devos et al,
2009
96% of patients
improved
95% of patients
improved
Honig et al, 2009
73% of patients
improved in item
39 of UPDRS
- 67% (relative
change of items 3235 of UPDRS)
Devos D, et al. Mov Disorder 2009;24:993-1000. Honig H, et al. Mov Disorder 2009;24:1468-74.
Patients
(N)
Time
91
Up to 4 y
22
6m
DIREQT study results:
Video scoring, functional ‘on’ time
Adapted from Nyholm D, et al. Neurology 2005;64:216-23. Reproduced with permission of the American Academy of Neurology. Clinical Study Report
NPP-000-02, data on file at Abbott.
DIREQT study results:
UPDRS total scores
Adapted from Nyholm D, et al. Neurology 2005;64:216-23. Reproduced with permission of the American Academy of Neurology. Clinical Study Report
NPP-000-02, data on file at Abbott
Long-term effect of duodenal
carbidopa/levodopa gel infusion
Time per day with moderate-to-severe ‘off’
Puente V, et al. Parkinsonism Relat Disord 2010;16:218-21.
Long-term effect of duodenal
carbidopa/levodopa gel infusion
Time per day with moderate-to-severe dyskinesias
Antonini A, et al. Duodenal levodopa infusion for advanced Parkinson's disease: 12-month treatment outcome. Movement Disorders Vol. 22, No.
8 2007, p1145-9. Copyright (2007 Movement Disorder Society); Reproduced with permission of John Wiley & Sons, Inc.
German experience with duodenal
carbidopa/levodopa gel infusion
Data from 2005–2006
Adapted from Eggert K, et al. Clinical Neuropharm 2008;31:151-66.
German experience with duodenal
carbidopa/levodopa gel infusion
Data from 2005–2006
Adapted from Eggert K, et al. Clinical Neuropharm 2008;31:151-66.
Effect of duodenal carbidopa/levodopa
gel infusion on non-motor symptoms
Effect size ≥0.8 is indicative of a large effect
Follow-up measurement after 6 months of treatment
Honig H, et al. Mov Disord 2009;24:1468-74. Copyright (2009 Movement Disorder Society); Reproduced with permission of John Wiley & Sons, Inc.
Cognitive improvement with duodenal
carbidopa/levodopa gel infusion
Cognitive improvement after duodenal carbidopa/levodopa gel infusion in two cognitively impaired patients
Patient 1
Patient 2
Pre-DLI
Post-DLI
(24 m followup)
Pre-DLI
Post-DLI
(2 m follow-up)
MMSE
17/30
23/30
25/30
28/30
Total Matis DRS score (maximum
144)
102
impaired
124 normal
Attention (max37)
35 normal
35 normal
Learning
2,4 and 5
impaired
3,5 and 8
normal
Indication/preservation (max37)
23 impaired
23 impaired
Delayed recall
2 impaired
6 normal
Construction (max 6)
3 impaired
5 normal
Recognition
12/20
impaired
20/20 normal
Conceptualisation (max 39)
24 impaired
38 normal
Inhibition (Stroop test
interference score)
- 9.56
impaired
- 0.16 normal
Memory (max 25)
17 impaired
23 normal
Flexibility (TMT-A)
Impaired
normal
Attention
(digit span forwards)
4 impaired
6 normal
Cerad memory scale
Phonetic verbal fluency
6 impaired
12 normal
6 impaired
12 normal
Category verbal fluency
7 impaired
9 mild
impairment
6 impaired
12 normal
Adapted from: Sánchez-Castañeda C, et al. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:250-1.
Duodenal carbidopa/levodopa gel infusion:
Effects on quality of life
Study
Scale
Baseline
Duodopa
Follow-up
Nyholm et al, 2005
PDQ-39
(median)
35
25**
3w
15D
0.72
0.78**
Antonini et al, 2007 PDQ-39
Significant improvement in 4/8
subscales
1y
Antonini et al, 2008 PDQ-39
60
49**
2y
Honig et al, 2009
PDQ-8
44
21**
6m
Puente et al, 2010
PDQ-39 (mean)
73
46*
18 m
*P<0.05 **P<0.01
PDQ-8 and PDQ-39: low value = high quality of life
15D: high value = high quality of life
Nyholm D, et al. Neurology 2005;64:216-23. Antonini A, et al. Mov Disord 2007;22:1145-9. Antonini A, et al. Neurodegenerative Dis 2008;5:244-6.
Honig H, et al. Mov Disord 2009;24:1468-74. Puente V, et al. Parkinsonism Relat Disord 2010;16:218-21.
Duodenal carbidopa/levodopa gel infusion:
Improvements in quality of life
Change in PDQ-8 scores induced by duodenal carbidopa/levodopa
gel infusion treatment
Honig H, et al. Mov Disord 2009;24:1468-74.
Effect of duodenal carbidopa/levodopa gel
infusion on patient-rated quality of life
Percentages represent the proportion of the population concerned, as assessed
by the patient and caregiver on a 5-point scale at the last examination
Devos D, et al. Mov Disord 2009;24:993-1000.
Effect of duodenal carbidopa/levodopa gel
infusion on patient-rated quality of life
Agree completely
(%)
Agree in
part (%)
Disagree
completely (%)
Improved mood
44
40
16
More active
36
32
32
Improved quality of
life
76
24
0
Improved functioning
84
16
0
Relatives’ opinion on
improved functioning
80
16*
0
* One case of attrition, i.e., N=24
“Ninety-six percent of the 25 patients interviewed strongly
recommend the infusion to someone else.”
Scott B, Nyholm D. European Neurological Journal 2010;2:1-8.
Duodenal carbidopa/levodopa gel infusion:
Overview of adverse events (medical)
Duration
N
Severe
psychosis
after 1 w
Hallucinations
and marked
confusion after
1m
Hallucinations
Confusion
Delusions
8
2
GuillainBarre
syndrome
Retrospective studies
Nyholm
et al, 2008*
12 m
58
Devos
et al, 2009
Up to 4 y
91
6
2
Prospective studies
Antonini
et al, 2007
12m
9
Puente
et al, 2010
18m
9
Total
167
1
2
1
1
6
8
2
* >5 events in any group
>1 event may have occurred in each patient
Antonini A, et al. Mov Disord 2007;22:1145-9. Nyholm D, et al. Clin Neuropharmacol 2008;31:67-73. Devos D, et al. Mov Disord
2009;24:993-1000. Puente V, et al. Parkinsonism Relat Disord 2010;16:218-21.
1
DIREQT study results:
Adverse events (medical)
Signs and symptoms
Baseline, %
(N=65)
First year of follow-up, %
(N=58)
Agitation
4.6
3.4
Anxiety
30.8
20.7
Confusion
6.2
13.8
Sedation
7.7
8.6
Delusions
6.2
3.4
Depression
16.9
5.2
Hallucinations
16.9
10.3
Reduced night time sleep
and sleep fragmentation
44.6
39.7
Sudden onset of sleep
1.5
0
Dyskinesia
93.8
93.1
Dystonia
32.3
15.5
Freezing
46.2
22.4
Headache
0
3.4
Restless legs syndrome, aches, cramps
9.2
8.6
Psychiatric disorders
Neurological disorders
Nyholm D, et al. Clin Neuropharmacol 2008;31:67-73. Reproduced with permission of Lippincott, Williams & Wilkins.
DIREQT study results:
Adverse events (medical)
Signs and symptoms
Baseline, % (N=65)
First year of follow-up, %
(N=58)
Autonomic nervous system disorders
Anorexia
7.7
5.2
Constipation
33.8
31.0
Diarrhoea
1.5
1.7
Nausea/vomiting
4.6
10.3
Orthostatic dizziness
10.8
6.9
Palpitation/tachycardia
0
1.7
Sweating
10.8
13.8
Nyholm D, et al. Clin Neuropharmacol 2008;31:67-73. Reproduced with permission of Lippincott, Williams & Wilkins.
DIREQT study results:
Adverse events (medical)
Signs and symptoms
Baseline, % (N=65)
First year of follow-up, %
(N=58)
Cramp legs
4.6
6.9
Dizziness
0
3.4
Dysarthia
3.1
5.2
Dysphagia
3.1
0
Fainting
1.5
5.2
Falls
9.2
6.9
Impaired memory
3.1
1.7
Nightmares
9.2
5.2
Pain in hip/leg/foot
0
6.9
Urinary incontinence
1.5
0
Vivid dreams
0
1.7
Others
Nyholm D, et al. Clin Neuropharmacol 2008;31:67-73. Reproduced with permission of Lippincott, Williams & Wilkins.
Duodenal carbidopa/levodopa gel infusion:
Technical complications (device-related)
Duration
N
Peritonitis
(post-op.)
Subdiaphrag
-matic
abscess
(post-op.)
Transien
t,
benign,
local
treated
infection
Persistent,
benign
local
inflammation
Transien
t, benign,
local
inflamma
-tion
Any
problem
with
stoma
Tube
connectors
broken
Retrospective studies
Nyholm
et al, 2008
1–10.7 y
49
Devos
et al, 2009
Up to 4 y
91
1
4
29
9
2
3
18
Prospective studies
Antonini
et al, 2007
12 m
9
Puente
et al, 2010
18 m
9
Total
158
9*
4
1
9
2
3
47
15
*15 occasions were reported in total
Adapted from ; Antonini A, et al. Mov Disord 2007;22:1145-9. Nyholm D, et al. Clin Neuropharmacol 2008;31:67-73. Devos D, et al. Mov
Disord 2009;24:993-1000. Puente V, et al. Parkinsonism Relat Disord 2010;16:218-21.
Duodenal carbidopa/levodopa gel infusion:
Technical complications (device-related), continued
Duration
N
Any
problem
with PEG
tube
16
Inner tube
disconnected,
leakage
Inner
tube
pulled
out
Inner tube
obstructed
Inner tube
dislocated
Any
problem
with inner
tube
Pump
failure
47
12
57
5
Retrospective studies
Nyholm
et al, 2008
1–10.7 y
49
Devos
et al, 2009
Up to 4 y
91
18
16
15
19
Prospective studies
Antonini
et al, 2007
12 m
9
Puente
et al, 2010
18 m
9
9*
158
16
Total
3
18
16
18
3
9*
9*
30
118
* 11 occasions were reported in total
Adapted from ; Antonini A, et al. Mov Disord 2007;22:1145-9. Nyholm D, et al. Clin Neuropharmacol 2008;31:67-73. Devos D, et al. Mov
Disord 2009;24:993-1000. Puente V, et al. Parkinsonism Relat Disord 2010;16:218-21.
17
Tube system
1991-2002; N=65
Pump
Intestinal
tube
Stoma
PEG tube
Patients with problems, n(%)
8 (16)
34 (69)
18 (37)
3 (6)
Number of times/patients with
complication
1–2
1–8
1–4
1–2
Patients with problems, n (%)
12 (24)
47 (96)
29 (59)
16 (33)
Number of times/patients with
complication
1–3
1–12
1–3
1–5
First year
Total follow-up
”...mean number of tube dislocations decreased from 2.6 to 0.7 events during the second year (P < 0.0001) /---/
Device problems were a contributing reason for discontinuation of the treatment for at least 11 patients.”
Technical problems can lead to discontinuations, but improvements in technical aspects of the tube and connector,
and increased patient/carer experience reduce the risk of this complication over time
Nyholm D, et al. Clin Neuropharmacol 2008;31:67-73: Reproduced with permission of Lippincott, Williams & Wilkins.
Tube system, continued
2003-2007; N=91
Frequency
(N)
Adverse events
Frequency
(N)
Leading to
discontinuation
Related to levodopa
treatment
2.2% (2)
Severe psychosis induction within a week
of starting treatment
2.2% (2)
2.2% (2)
Related to
gastrostomy
18% (18)
Peritonitis
4.3% (4)
No
Transient, benign, local treated infection
9.8% (9)
1% (1)
Persistent, benign, local inflammation
2.2% (2)
No
Transient, benign, local inflammation
3.3% (3)
No
Pump failure
5.5% (5)
No
Inner tube disconnected responsible for
leakage
19.8% (18)
No
Inner tube pulled out due to severe motor
handicap or dementia
17.5% (16)
3.3% (3)
Inner tube obstructed
16.5% (15)
No
Inner tube dislocated with secondary
migration in the intestine
20.8% (19)
3.3% (3)
Related to technical
aspects and requiring
replacement
62.6% (57)
One or more technical problems were noted in 62.6% (N=57) of the patients. Technical aspects led to discontinuation in six patients.
Devos D, et al. Mov Disord 2009;24:993-1000:Copyright (2009 Movement Disorder Society); Reproduced with permission of John Wiley & Sons, Inc.
Duodenal carbidopa/levodopa gel infusion:
Benefits and limitations
Continuous delivery
Improved quality of life
Improved non-motor symptom control
Improved motor symptom control
Predictable effect
Not dependent on gastric emptying
Less ‘wearing-off’
Invasive method (PEG surgery)
Monotherapy
Patient depends on pump
Fewer and milder dyskinesias
Technical problems
Benefits
Limitations
Summary
• Intraduodenal infusion of carbidopa/levodopa ensures
continuous drug delivery, reduces motor fluctuations and
dyskinesia in Parkinson’s disease
• Continuous carbidopa/levodopa infusion is clinically superior to
a number of individually optimized combinations of conventional
oral medications in patients suffering from motor fluctuations
and dyskinesias
• Duodenal carbidopa/levodopa gel infusion treatment offers an
important alternative in the treatment of patients with advanced
Parkinson's disease