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

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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

Obeso J, et al. Trends Neurosci 2000;23(suppl):S1-S19.

Multiple versus continuous dosing ofduodenal 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 ofduodenal carbidopa/levodopa gel infusion

Continuous dosing of carbidopa/levodopa gel infusion is associated with more normal motor functioning

Endoscopic placement of PEG

Intestinal access

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

Patients (N) Time Functional

‘on’ time‘Off’

timeDyskinesia

Nilsson et al, 1998 + 24

+ 26

- 5

- 23

- 19

- 4

7

2

6 m

2.5 yNilsson et al, 2001 + 13 + 7* - 21 6 4–7 y

Nyholm et al, 2003 + 19 - 13 - 6 12 3 w

Nyholm et al, 2005 + 16 - 17 + 2 24 3 w

Antonini et al, 2007 + 42 - 28 - 13 7 1 y

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.

Study

Change in motor state with duodenal carbidopa/levodopa gel infusion Patients

(N)Time

‘Off’ Dyskinesia

Devos et al, 2009

96% of patients improved

95% of patients improved

91 Up to 4 y

Honig et al, 2009 73% of patients improved in item 39 of UPDRS

- 67% (relative change of items 32-35 of UPDRS)

22 6 m

Devos D, et al. Mov Disorder 2009;24:993-1000. Honig H, et al. Mov Disorder 2009;24:1468-74.

Duodenal carbidopa/levodopa gel infusion: Overview of clinical efficacy, continued

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:Video scoring, functional ‘on’ time

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

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 ‘off’

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.

Time per day with moderate-to-severe dyskinesias

Long-term effect of duodenal carbidopa/levodopa gel infusion

German experience with duodenal carbidopa/levodopa gel infusion

Adapted from Eggert K, et al. Clinical Neuropharm 2008;31:151-66.

Data from 2005–2006

Adapted from Eggert K, et al. Clinical Neuropharm 2008;31:151-66.

Data from 2005–2006

German experience with duodenal carbidopa/levodopa gel infusion

Honig H, et al. Mov Disord 2009;24:1468-74. Copyright (2009 Movement Disorder Society); Reproduced with permission of John Wiley & Sons, Inc.

Effect of duodenal carbidopa/levodopa gel infusion on non-motor symptoms

Effect size ≥0.8 is indicative of a large effectFollow-up measurement after 6 months of treatment

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 follow-up)

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 Cerad memory scale

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

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.

Study Scale Baseline Duodopa Follow-up

Nyholm et al, 2005 PDQ-39 (median)

35 25** 3 w

15D 0.72 0.78**

Antonini et al, 2007 PDQ-39 Significant improvement in 4/8 subscales

1 y

Antonini et al, 2008 PDQ-39 60 49** 2 y

Honig et al, 2009 PDQ-8 44 21** 6 m

Puente et al, 2010 PDQ-39 (mean) 73 46* 18 m

PDQ-8 and PDQ-39: low value = high quality of life

15D: high value = high quality of life

*P<0.05 **P<0.01

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:Effects on quality of life

Honig H, et al. Mov Disord 2009;24:1468-74.

Change in PDQ-8 scores induced by duodenal carbidopa/levodopagel infusion treatment

Duodenal carbidopa/levodopa gel infusion:Improvements in quality of life

Devos D, et al. Mov Disord 2009;24:993-1000.

Percentages represent the proportion of the population concerned, as assessed by the patient and caregiver on a 5-point scale at the last examination

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

Scott B, Nyholm D. European Neurological Journal 2010;2:1-8.

“Ninety-six percent of the 25 patients interviewed strongly recommend the infusion to someone else.”

Effect of duodenal carbidopa/levodopa gel infusion on patient-rated quality of life

Duration N Severe psychosis after 1 w

Hallucinations and marked confusion after 1 m

Hallucinations Confusion Delusions Guillain-Barre syndrome

Retrospective studies

Nyholm et al, 2008*

12 m 58 6 8 2

Devos et al, 2009

Up to 4 y 91 2

Prospective studies

Antonini et al, 2007

12m 9 1 1

Puente et al, 2010

18m 9

Total 167 2 1 6 8 2 1

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.

* >5 events in any group

>1 event may have occurred in each patient

Duodenal carbidopa/levodopa gel infusion:Overview of adverse events (medical)

Nyholm D, et al. Clin Neuropharmacol 2008;31:67-73. Reproduced with permission of Lippincott, Williams & Wilkins.

Signs and symptoms Baseline, % (N=65)

First year of follow-up, % (N=58)

Psychiatric disorders

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

Neurological disorders

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

DIREQT study results:Adverse events (medical)

Nyholm D, et al. Clin Neuropharmacol 2008;31:67-73. Reproduced with permission of Lippincott, Williams & Wilkins.

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

DIREQT study results:Adverse events (medical)

Nyholm D, et al. Clin Neuropharmacol 2008;31:67-73. Reproduced with permission of Lippincott, Williams & Wilkins.

Signs and symptoms Baseline, % (N=65) First year of follow-up, % (N=58)

Others

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

DIREQT study results:Adverse events (medical)

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.

*15 occasions were reported in total

Duodenal carbidopa/levodopa gel infusion:Technical complications (device-related)

Duration N Peritonitis (post-op.)

Subdiaphrag-matic abscess (post-op.)

Transient, benign, local treated infection

Persistent, benign local inflamma-tion

Transient, benign, local inflamma-tion

Any problem with stoma

Tube connectors broken

Retrospective studies

Nyholm et al, 2008

1–10.7 y 49 1 29

Devos et al, 2009

Up to 4 y 91 4 9 2 3 18

Prospective studies

Antonini et al, 2007

12 m 9

Puente et al, 2010

18 m 9 9*

Total 158 4 1 9 2 3 47 15

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.

* 11 occasions were reported in total

Duration N Any problem with PEG tube

Inner tube disconnected, leakage

Inner tube pulled out

Inner tube obstructed

Inner tube dislocated

Any problem with inner tube

Pump failure

Retrospective studies

Nyholm et al, 2008

1–10.7 y 49 16 47 12

Devos et al, 2009

Up to 4 y 91 18 16 15 19 57 5

Prospective studies

Antonini et al, 2007

12 m 9 3 3

Puente et al, 2010

18 m 9 9* 9* 9*

Total 158 16 18 16 18 30 118 17

Duodenal carbidopa/levodopa gel infusion:Technical complications (device-related), continued

Tube system

1991-2002; N=65 Pump Intestinal tube

Stoma PEG tube

First year

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

Total follow-up

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

Nyholm D, et al. Clin Neuropharmacol 2008;31:67-73: Reproduced with permission of Lippincott, Williams & Wilkins.

”...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

Tube system, continued

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.

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

Related to technical aspects and requiring replacement

62.6% (57) 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)

Duodenal carbidopa/levodopa gel infusion: Benefits and limitations

Improved non-motor symptom control

Improved motor symptom control

Predictable effect

Not dependent on gastric emptying

Less ‘wearing-off’

Monotherapy

Fewer and milder dyskinesias

Invasive method (PEG surgery)

Patient depends on pump

Technical problems

Benefits Limitations

Continuous delivery

Improved quality of life

• 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

Summary