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Evidence-based review of current Parkinson’s disease treatments This educational material has been supported by Abbott.

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Presentation on theme: "Evidence-based review of current Parkinson’s disease treatments This educational material has been supported by Abbott."— Presentation transcript:

1 Evidence-based review of current Parkinson’s disease treatments This educational material has been supported by Abbott

2 Evidence-based review of current Parkinson’s disease treatments Duodenal carbidopa/levodopa gel infusion treatment >

3 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

4 Obeso J, et al. Trends Neurosci 2000;23(suppl):S1-S19. Multiple versus continuous dosing of duodenal carbidopa/levodopa gel infusion Multiple dosing of levodopa is associated with increased risk of motor complications

5 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

6 Endoscopic placement of PEG Intestinal access

7 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

8 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’ time Dyskinesia Nilsson et al, 1998 + 24 + 26 - 5 - 23 - 19 - 4 7 2 6 m 2.5 y Nilsson 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.

9 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 91Up 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) 226 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

10 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

11 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

12 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’

13 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

14 German experience with duodenal carbidopa/levodopa gel infusion Adapted from Eggert K, et al. Clinical Neuropharm 2008;31:151-66. Data from 2005–2006

15 Adapted from Eggert K, et al. Clinical Neuropharm 2008;31:151-66. Data from 2005–2006 German experience with duodenal carbidopa/levodopa gel infusion

16 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 effect Follow-up measurement after 6 months of treatment

17 Cognitive improvement with duodenal carbidopa/levodopa gel infusion Cognitive improvement after duodenal carbidopa/levodopa gel infusion in two cognitively impaired patients Patient 1Patient 2 Pre-DLIPost-DLI (24 m follow- up) Pre-DLIPost-DLI (2 m follow-up) MMSE17/3023/3025/3028/30 Total Matis DRS score (maximum 144) 102 impaired 124 normalCerad memory scale Attention (max37)35 normal Learning2,4 and 5 impaired 3,5 and 8 normal Indication/preservation (max37)23 impaired Delayed recall2 impaired6 normal Construction (max 6)3 impaired5 normalRecognition12/20 impaired 20/20 normal Conceptualisation (max 39)24 impaired38 normalInhibition (Stroop test interference score) - 9.56 impaired - 0.16 normal Memory (max 25)17 impaired23 normalFlexibility (TMT-A)Impairednormal Attention (digit span forwards) 4 impaired6 normal Phonetic verbal fluency6 impaired12 normal6 impaired12 normal Category verbal fluency7 impaired9 mild impairment 6 impaired12 normal Adapted from: Sánchez-Castañeda C, et al. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:250-1.

18 StudyScaleBaselineDuodopaFollow-up Nyholm et al, 2005PDQ-39 (median) 3525**3 w 15D0.720.78** Antonini et al, 2007PDQ-39Significant improvement in 4/8 subscales 1 y Antonini et al, 2008PDQ-396049**2 y Honig et al, 2009PDQ-84421**6 m Puente et al, 2010PDQ-39 (mean)7346*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

19 Honig H, et al. Mov Disord 2009;24:1468-74. Change in PDQ-8 scores induced by duodenal carbidopa/levodopa gel infusion treatment Duodenal carbidopa/levodopa gel infusion: Improvements in quality of life

20 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

21 Agree completely (%) Agree in part (%) Disagree completely (%) Improved mood444016 More active3632 Improved quality of life 76240 Improved functioning84160 Relatives’ opinion on improved functioning 8016 * 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

22 DurationNSevere psychosis after 1 w Hallucinations and marked confusion after 1 m HallucinationsConfusionDelusionsGuillain- Barre syndrome Retrospective studies Nyholm et al, 2008* 12 m58682 Devos et al, 2009 Up to 4 y912 Prospective studies Antonini et al, 2007 12m911 Puente et al, 2010 18m9 Total167216821 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)

23 Nyholm D, et al. Clin Neuropharmacol 2008;31:67-73. Reproduced with permission of Lippincott, Williams & Wilkins. Signs and symptomsBaseline, % (N=65) First year of follow-up, % (N=58) Psychiatric disorders Agitation4.63.4 Anxiety30.820.7 Confusion6.213.8 Sedation7.78.6 Delusions6.23.4 Depression16.95.2 Hallucinations16.910.3 Reduced night time sleep and sleep fragmentation 44.639.7 Sudden onset of sleep1.50 Neurological disorders Dyskinesia93.893.1 Dystonia32.315.5 Freezing46.222.4 Headache03.4 Restless legs syndrome, aches, cramps9.28.6 DIREQT study results: Adverse events (medical)

24 Nyholm D, et al. Clin Neuropharmacol 2008;31:67-73. Reproduced with permission of Lippincott, Williams & Wilkins. Signs and symptomsBaseline, % (N=65)First year of follow-up, % (N=58) Autonomic nervous system disorders Anorexia7.75.2 Constipation33.831.0 Diarrhoea1.51.7 Nausea/vomiting4.610.3 Orthostatic dizziness10.86.9 Palpitation/tachycardia01.7 Sweating10.813.8 DIREQT study results: Adverse events (medical)

25 Nyholm D, et al. Clin Neuropharmacol 2008;31:67-73. Reproduced with permission of Lippincott, Williams & Wilkins. Signs and symptomsBaseline, % (N=65)First year of follow-up, % (N=58) Others Cramp legs4.66.9 Dizziness03.4 Dysarthia3.15.2 Dysphagia3.10 Fainting1.55.2 Falls9.26.9 Impaired memory3.11.7 Nightmares9.25.2 Pain in hip/leg/foot06.9 Urinary incontinence1.50 Vivid dreams01.7 DIREQT study results: Adverse events (medical)

26 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) DurationNPeritonitis (post-op.) Subdiaphrag -matic abscess (post-op.) Transien t, benign, local treated infection Persistent, benign local inflamma- tion Transien t, benign, local inflamma -tion Any problem with stoma Tube connectors broken Retrospective studies Nyholm et al, 2008 1–10.7 y49129 Devos et al, 2009 Up to 4 y91492318 Prospective studies Antonini et al, 2007 12 m9 Puente et al, 2010 18 m99* Total158419234715

27 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 DurationNAny 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 y49164712 Devos et al, 2009 Up to 4 y9118161519575 Prospective studies Antonini et al, 2007 12 m933 Puente et al, 2010 18 m99* Total158161816183011817 Duodenal carbidopa/levodopa gel infusion: Technical complications (device-related), continued

28 Tube system 1991-2002; N=65PumpIntestinal tube StomaPEG tube First year Patients with problems, n(%)8 (16)34 (69)18 (37)3 (6) Number of times/patients with complication 1–21–81–41–2 Total follow-up Patients with problems, n (%)12 (24)47 (96)29 (59)16 (33) Number of times/patients with complication 1–31–121–31–5 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

29 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=91Frequency (N) Adverse eventsFrequency (N) Leading to discontinuation Related to levodopa treatment 2.2% (2)Severe psychosis induction within a week of starting treatment 2.2% (2) Related to gastrostomy 18% (18)Peritonitis4.3% (4)No Transient, benign, local treated infection9.8% (9)1% (1) Persistent, benign, local inflammation2.2% (2)No Transient, benign, local inflammation3.3% (3)No Related to technical aspects and requiring replacement 62.6% (57)Pump failure5.5% (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 obstructed16.5% (15)No Inner tube dislocated with secondary migration in the intestine 20.8% (19)3.3% (3)

30 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 BenefitsLimitations Continuous delivery Improved quality of life

31 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


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