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carbidopa in advanced Parkinson’s disease
Basal Ganglia 5 (2015) 95–99
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Basal Ganglia journal homepage: www.elsevier.com/locate/baga
New developments in continuous jejunal infusion of levodopa/ carbidopa in advanced Parkinson’s disease Jens Carsten Möller* , Matthias Oechsner Parkinson Center, Center for Neurological Rehabilitation, Hauptstrasse 2-4, 8588 Zihlschlacht, Switzerland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 July 2015 Received in revised form 1 October 2015 Accepted 1 October 2015
Levodopa-associated motor fluctuations and dyskinesia in patients with Parkinson's disease (PD) are often difficult to control by the oral administration of levodopa. Continuous infusion of a levodopa/ carbidopa intestinal gel (LCIG) may represent a feasible treatment option for this patient population. To start LCIG infusion, a temporary nasoduodenal/nasojejunal tube should be considered to show that the patient responds favorably, before a permanent percutaneous endoscopic gastrostomy with jejunal tube (PEG-J) is placed. The present review focuses on recently published key studies on the efficacy and safety of LCIG treatment in advanced PD. The results provide robust evidence of a marked reduction of OFFfluctuations and dyskinesia, thereby also improving the quality of life of these severely disabled patients. LCIG treatment is therefore a promising alternative to continuous subcutaneous apomorphine infusion or deep brain stimulation in advanced PD patients with severe motor fluctuations. ã 2015 Elsevier GmbH. All rights reserved.
Keywords: Duodopa1 Duopa1 Motor complications Non-motor symptoms Quality of life Treatment adherence
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction . . . . . . Olanow et al. [6] . . Slevin et al. [8] . . . . Fernandez et al. [9] Antonini et al. [10] . Other recent studies Conclusions . . . . . . Acknowledgments . References . . . . . . .
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1. Introduction Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder and characterized by the motor symptoms akinesia, rigidity, rest tremor, and postural instability as well as a range of non-motor symptoms. Although the oral symptomatic treatment of motor symptoms in PD has been improved during the previous decades, the gold standard for the therapy of motor symptoms remains levodopa in combination with an inhibitor of aromatic amino acid decarboxylation such as carbidopa. However,
* Corresponding author. E-mail addresses: [email protected] (J.C. Möller), [email protected] (M. Oechsner). http://dx.doi.org/10.1016/j.baga.2015.10.001 2210-5336/ ã 2015 Elsevier GmbH. All rights reserved.
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95 96 96 96 98 98 99 99 99
levodopa-associated motor fluctuations and dyskinesia often pose a major challenge in advanced PD and are difficult to control by the oral administration of levodopa. Alternatives include, e.g., continuous subcutaneous apomorphine infusion (CSAI), deep brain stimulation, and continuous intestinal infusion of levodopa/ carbidopa by means of a gel (LCIG, Duodopa1 in Europe; Duopa1 in the US) [1]. Apart from the continuous drug delivery achieved with LCIG by the direct administration into the small intestine, the stomach passage can be avoided, which may otherwise lead to insufficient active substance absorption due to PD-related irregular gastric emptying [2]. The placement of the intestinal tube (i.e., PEG-J) for LCIG requires surgery with only local anesthesia by most gastroenterology departments. The PEG-J is usually performed after a test phase with a transnasal jejunal tube over several days. Nasal titration is not required in Europe and in the recently issued
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FDA approval for Duopa1, but recommended in Switzerland [3–5]. Duodopa1/Duopa1 is indicated for the treatment of advanced levodopa/responsive PD with severe motor fluctuations and hyper-/dyskinesia when available combinations of Parkinson medicinal products have not given satisfactory results. The present review focuses on new developments with respect to LCIG infusion in advanced PD with special emphasis on four recently published clinical trials. 2. Olanow et al. [6] The randomized, double-blind, double-dummy, double-titration HORIZON study included 71 patients with advanced PD, who did not achieve satisfactory control of OFF-times with optimized drug therapy (oral levodopa/carbidopa, dopamine agonist and at least one other PD medication) (Table 1) [6]. Participants received stable doses of levodopa for at least 4 weeks before enrolment in the study and had at least 3 h of OFF-time per day as measured by a home diary. Subjects receiving sustained-release levodopa/carbidopa, Stalevo1 (Orion Pharma, Finland), or other formulations of levodopa were permitted after conversion to equivalent doses of immediate-release levodopa/carbidopa at least 4 weeks before study entry. Additional PD medication was permitted, provided that its dosage had remained stable for 4 weeks prior to randomization and no dose adjustments were made during the study. Subjects were randomized to treatment with LCIG plus oral placebo or to oral levodopa/carbidopa plus placebo intestinal gel. Compared to baseline, the mean daily OFF-time as primary outcome measure was reduced by 4.04 h/d (standard error [SE] 0.65) in the LCIG group and by 2.14 h/d (SE 0.66) in the placebo group. This difference was highly significant in favor of LCIG treatment (p = 0.0015). At the same time, ON-time without troublesome dyskinesia as secondary outcome measure was increased in the LCIG group by 4.11 h/d (SE 0.75) vs. 2.24 h/d (SE 0.76) in the placebo group (p = 0.0059). The Parkinson Disease Questionnaire-39 (PDQ-39) Summary Index values were reduced as compared to the baseline value by 10.9 points (SE 3.3) in the LCIG group and by 3.9 points (SE 3.2) in the placebo group (p = 0.0155). Furthermore, the mean score on the Clinical Global Impression-Improvement (CGI-I) scale (7-point scale from 1 = very much improved to 7 = very much worse) was 2.3 points (SE 0.4) in the LCIG group and 3.0 points (SE 0.4) in the placebo group at the final examination (p = 0.026). Although almost all study subjects experienced adverse effects (95% in the LCIG group, 100% in the placebo group), that occurred mainly as a result of the tube placement, most were temporary and limited to the first week following PEG-J tube placement. Four of the 71 patients showed signs of polyneuropathy (1 in the LCIG group, 3 in the placebo group). No cases of Guillain-Barré syndrome were observed [6]. 3. Slevin et al. [8] In contrast to the HORIZON study design, in which no dose adjustments were permitted after the titration phase, continuous adjustment of the LCIG dose is standard practice in Europe. This practice corresponds to the protocol of the 1-year, open-label HORIZON extension study published by Slevin et al. [8] (Table 1). Prior to a new titration phase, the LCIG-naive group that received placebo during the HORIZON study was switched to LCIG. Due to tapering of the other PD medication and the continuous LCIG dose adjustment, 65% of all patients were treated with a levodopa monotherapy consisting of LCIG with or without oral levodopa during the night at the end of the study. In the LCIG-naive patients, start of LCIG infusion led to a mean OFF-time reduction of 2.34 h/d (SD 2.78; p < 0.001) starting from BL 5.08 h/d (SD 2.03), while in
the LCIG-treated group (patients treated with LCIG during the HORIZON study), continuation of LCIG resulted in a moderate mean reduction from BL 3.11 h/d (SD 2.56) of 0.42 h/d (SD 2.67; p = 0.377). Interestingly, the combined effect on OFF-time in the pivotal trial plus extension was the same for both groups irrespective of early versus later start of LCIG-treatment. During both consecutive studies, OFF-time with 6.3 h/d (SD 1.7) at BL decreased 4.04 h/d (SE 0.65) and 0.42 h/d (SD 2.67) in the LCIGgroup versus the LCIG-naïve group where OFF-time with 7.0 h/d (SD 2.1) at BL decreased 2.14 h/d (SE 0.66) and 2.34 h/d (2.78), respectively. The mean increase of ON-time without troublesome dyskinesia was 2.19 h/d (SD 3.7; p = 0.005) in the LCIG-naive and 1.0 h/d (SD 2.58; p = 0.036) in the LCIG-treated group. The improvement in the LCIG-treated group is possibly explained by the fact that the LCIG dose was optimized at the start of the extension study and that dose adjustments were now permitted throughout the entire study duration (Table 1). No significant changes to quality of life were observed during the extension study. However, the CGI-I score showed significant improvement in both groups (by 2 points each; p < 0.001) and the majority of patients improved very much (40%), much (>27%) or minimally (>13%). It was possible to assess the safety of LCIG independently of complications caused by the tube placement, as the duodenal tube had already been placed during the HORIZON study, 12 weeks prior to the start of the extension study [6]. With regard to the incidence of potential levodopa-associated adverse effects such as dyskinesia, hallucinations and orthostatic hypotension, no difference was observed between the LCIG-treated and LCIG-naive groups during the first 4 weeks. 77% of patients experienced adverse effects possibly or probably related to the treatment. However, these were generally mild to moderate. The incidence of adverse effects continuously decreased over the course of the study duration (from 52% to 24%, evaluation every 30 days). The most common serious adverse effects were complications associated with the tube placement (5%), abdominal pain (3%), asthenia (3%) and pneumonia (3%). A not severe polyneuropathy was observed in 9.7% of patients (3 LCIG-naive, 3 LCIG-treated), which is within the normal rates of polyneuropathy in PD [8]. Treatment adherence was high at 89% over the course of a year. 4. Fernandez et al. [9] The study design of the largest prospective open-label LCIG study (n = 354) by Fernandez et al. reflects standard procedure in Europe (Table 1) [9]. In this study, the initial LCIG monotherapy dosage was determined via nasal titration. Additional PD medication was only permitted after subsequent dose titration (in this case, 28 days after PEG-J placement) and dose adjustments were permitted throughout the entire study duration. The final data confirm the results of the HORIZON study. The mean daily OFFtime was reduced by 65.6%, i.e., by 4.4 h/d (SD 2.9; p < 0.001), and the ON-time without troublesome dyskinesia increased by 62.9%, i.e., by 4.8 h/d (SD 3.4; p < 0.001). These improvements persisted throughout the entire treatment duration of 54 weeks. Furthermore, the CGI-I score showed that 22.4% of patients were very much improved, 55.5% were much improved and 13.7% were minimally improved. 3.1% of patients showed no change; 2.8% reported to be minimally worse and 1.0% to be much worse. The mean PDQ-39 Summary Index was 6.9 14.1 points lower than the baseline value. A statistically significant mean improvement was achieved in seven of the eight PDQ-39 dimensions, social support being the only exception [9]. It should also be noted that the daily dose remained stable after initial nasal titration (mean LCIG dose of 1572 mg/d at last visit), which indicates that no obvious LCIG
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97
Table 1 Study overview on LCIG (with permission from [7])
Patients included Inclusion criteria
Olanow et al. [6] HORIZON Pivotal Study
Slevin et al. [8] HORIZON extension study
Fernandez et al. [9] Open-label 12-month study
Antonini et al. [10] GLORIA 24-month study: 12-month interim analysis
n = 71
n = 62
n = 354
n = 172 Patients with advanced PD eligible for LCIG treatment according to local SPC and national reimbursement criteria
Positive response to levodopa Diagnosis according to UK Parkinson’s Disease Society Brain Bank criteria Severe motor fluctuations defined as 3 h/d OFF-time during baseline despite optimized oral PD treatment
Study design
Switch to immediate-release levodopa/carbidopa Tube placement Randomization to study arms: LCIG plus oral placebo or oral immediaterelease levodopa/carbidopa plus intestinal placebo gel Titration over the course of 4 weeks Overall study duration 12 weeks No LCIG dosage adjustment possible after titration Stable dosage of oral PD comedication during study
New adjustment of LCIG dose in LCIG-naive and LCIG-treated patients Initial dose according to optimized oral levodopa/carbidopa dose prior to randomization to the double-blind HORIZON study Titration for 1 week LCIG treatment over the course of 52 weeks LCIG dosage adjustment possible after titration Tapering of oral PD comedication possible during study
Nasojejunal titration 2–14 days LCIG titration 2–14 days LCIG treatment over the course of 54 weeks Individual dose adjustments possible during study Gradual introduction of oral PD comedication only permitted 28 days after PEG-J placement Oral immediate release levodopa/carbidopa only permitted during the night Apomorphine and controlledrelease levodopa/carbidopa not permitted
LCIG-naive patients Start of LCIG infusion by temporary nasoduodenal tube to test clinical response and perform titration of LCIG Dose should be adjusted to an optimal clinical response for each patient, which means maximizing the functional ONtime during the day by minimizing the OFF-time and ONtime with disabling dyskinesia. PEG-J placement and treatment with permanent tube over the course of 24 months Results presented from the 12month interim analysis
Mean age at baseline (years) Mean OFFtime (h/d) at BL Mean reduction of OFF-time (h/ d)
LCIG: 63.7 [SE 9.5] Placebo: 65.1 [SE 6.8]
LCIG-treated: 63.6 [SD 9.0] LCIG-naive: 64.8 [SD 6.6]
64.1 [SD 9.1]
66.5 [SD 9.3]
LCIG: 6.3 [SE 1.7] Placebo: 7.0 [SE 2.1]
LCIG-treated: 3.11 [SD 2.56] LCIG-naive: 5.08 [SD 2.03]
6.75 [SD 2.35]
7.1 [SD 3.5]
LCIG: 4.04 [SE 0.65] Placebo: 2.14 [SE 0.66]
LCIG-treated: 0.42 [SD 2.67; p=0.377] LCIG-naive: 2.34 [SD 2.78; p<0.001]
4.4 [SD 2.9; p < 0.001]
4.7 [SD 3.4; p < 0.0001]
LCIG: 8.7 [SE 2.0] Placebo: 7.8 [SE 2.5]
LCIG-treated: 11.83 [SD 2.68] LCIG-naive: 9.86 [SD 2.61]
7.65 [SD 2.45]
NA
LCIG: 4.11 [SE 0.75] Placebo: 2.24 [SE 0.76]
LCIG-treated: 1.00 [SD 2.58; p = 0.036] LCIG-naive: 2.19 [SD 3.7; p = 0.005]
4.8 [SD 3.4; p < 0.001]
NA
NA
NA
NA
5.2 [SD 4.5]
NA
NA
NA
1.7 [SD 5.0; p = 0.0228]
NA
NA
NA
75.3 [SD 42.2]
NA
NA
NA
22.2 [SD 50.6; p = 0.0014]
PDQ-39
PDQ-39
PDQ-39
PDQ-8
35.1 [SD 18.0]
LCIG-treated: 22.0 [SD 17.1] LCIG-naive: 32.1 [SD 17.2]
42.8 [SD 15.1]
48.6 [SD 19.0]
PDQ-39
PDQ-39
PDQ-39
PDQ-8
10.9 [SE 3.3; p = 0.0155]
LCIG-treated: sustained improvement
6.9 [SD 14.1 p<0.0001]
8.6 [SD 22.6; p=0.0100]
Mean ON-time without troublesome dyskinesia (h/d) at BL Mean increase of ON-time without troublesome dyskinesia (h/d) Mean ON-time with disabling dyskinesia (h/d) at BL Mean reduction of ON-time with disabling dyskinesia (h/d) NMSS Score at BL Mean reduction of NMSS Score Quality of Life: PDQ-8/39 Score at BL Mean reduction of PDQ-8/39 Score
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Table 1 (Continued) Olanow et al. [6] HORIZON Pivotal Study
Slevin et al. [8] HORIZON extension study
Fernandez et al. [9] Open-label 12-month study
Antonini et al. [10] GLORIA 24-month study: 12-month interim analysis
EQ-5D
EQ-5D
SI Score: 0.588 [SD 0.195] VAS Score: 50.2 [SD 21.0]
SI Score: 0.39 [SD 0.311] VAS Score: 47.3 [SD 20.9]
EQ-5D
EQ-5D
SI Score: 0.064 [SD 0.203; p < 0.0001] VAS Score: 14.0 [SD 24.8; p < 0.0001]
SI Score: 0.12 [SD 0.35; p = 0.0076] VAS Score: 15.6 [SD 24.7; p = 0.0001]
LCIG-naive: no significant improvement Quality of Life: EQ-5D Summary Index and VAS Score at BL Mean increase of EQ-5D Summary Index and VAS score
EQ-5D
NA
BL results not shown
EQ-5D
NA
LCIG: ns Placebo: ns
tolerance development took place. Administration rates of other PD medication were low and 76.5% of patients stayed on levodopa/ carbidopa monotherapy. Adverse effects were observed in 46.9% of patients during nasal titration. The most common adverse effects were insomnia (7.9%) and nasojejunal tube placement complications (7.3%) as well as oropharyngeal pain (6.5%). After conclusion of nasal titration, adverse effects were observed in 92% of patients receiving LCIG during the PEG-J phase. These were generally mild to moderate and transitory. Most common were tube placement complications (34.9%), pain during and after surgery (20.7%) and abdominal pain (31.2%) [9]. 5. Antonini et al. [10] The first interim data after a 12-month treatment duration of the international postmarketing surveillance study for Duodopa1 (GLORIA; n = 172) were published in early 2015 [10]. Patients were treated in accordance with the country-specific marketing authorization, whereby the LCIG dose was determined by the treating study physician and adjusted individually for each patient over the course of the study. The few exclusion criteria and the flexible dosage give the study practical relevance. After 12 months of treatment with LCIG, the daily OFF-time was reduced by 4.7 h/d (SD 3.4; p < 0.0001) and the ON-time with dyskinesia was reduced by 1.7 h/d (SD 5.0; p = 0.0228) as compared to baseline (Table 1). Severity coded of disabling Dyskinesia (UPDRS item 33) was reduced from 1.7 (SD 1.2) at BL to 0.9 (SD 1.2; p < 0.0001) and painful dyskinesia (UPDRS item 34) was reduced from 0.8 (SD 1.1) to 0.6 (SD 1.2; p = 0.0004). Non-motor symptoms (NMS) in PD are common and significantly reduce quality of life. One validated clinical tool to assess the progress or potential response to treatment of NMS had been developed with nine dimensions: cardiovascular, sleep/fatigue, mood/cognition, perceptual problems, attention/memory, gastrointestinal, urinary, sexual function, and miscellany [11]. The NMSS score diminished from 75.3 (SD 42.2) at BL by 22.2 points (SD 50.6; p = 0.0014), and improvements of non-motor symptoms were observed in 3 out of 9 NMSS domains to month 12, i.e., “Sleep/ Fatigue” (p = 0.0001), “Gastrointestinal tract” (p = 0.0096) and “Urinary” (p = 0.0199), while improvements in “Mood/Cognition” were evident to month 6 (p = 0.0426). PDQ-8 score improved by 8.6 (SD 22.6; p = 0.0100), and improvements of QoL were observed in 3 out of 8 PDQ-8 items to month 12, i.e., “Difficulty getting around in public places” (p = 0.0074), “Felt depressed” (p = 0.0372), and “Embarrassed by having PD” (p = 0.0312), while improvements in “Painful muscle cramps and pains” were evident to month 6
(p = 0.0031). The EQ-5D VAS Score improved to month 12 (p = 0.0001) and enhancement in the summary index score was evident to month 6 (p = 0.0076). The adverse effect profile was comparable to the results of other studies [10]. Results of two subgroup analysis from GLORIA performed with the interim data were presented at the 19th Annual International Congress of Parkinson’s Disease and Movement Disorders in June 2015 in San Diego: A.) Patients younger than 60 years old and with less than 10 years of Parkinson’s disease [12]: At BL, patients in this subgroup had a mean age of 52.5 (SD 5.7; n = 28) years and 6.1 (SD 1.9) years disease duration. OFF-time (8.0 h/d; SD 3.3) was longer and NMSS score was higher (76.3; SD 40.3) relative to the total population. After 12 months of LCIG treatment, the daily OFFtime was reduced by 6.7 h/d (SD 2.2; p < 0.0001) and the NMSS score by 32.9 points (SD 46.5; p < 0.05). In conclusion, LCIG treatment in younger patients with a relatively early disease stage resulted in a marked decrease of OFF-time and nonmotor symptoms comparable to the entire population (n = 343; age: 66.7, SD 8.4; disease duration: 12.8, SD 6.2). B.) Patients with >4 h/d dyskinesia [13]: The reduction from total time with dyskinesia at BL (7.2 h/d; SD 2.9; n = 114) was 3.0 h/d (SD 8.6; p = 0.0017) at month 12 (n = 86) and 3.0 (SD 5.9; p = 0.0339) at month 24 (n = 20). Duration of dyskinesia was reduced by more than 2 h/d in 69% of patients at month 12 and in 60% of patients at month 24. The reduction from PDQ-8 total score at BL (48.8; SD 19.6) was 16.6 (SD 24.2; p < 0.0001) at month 12 (n = 67) and 9.6 (SD 22.8; p = 0.1144) at month 24 (n = 16). In conclusion, advanced PD patients with pronounced dyskinesia at BL had a significant and long-term improvement in dyskinesia during LCIG treatment. The observed ADR profile in both subgroups was consistent with the established safety profile of LCIG [12,13]. 6. Other recent studies The prospective long-term data (n = 59) obtained over the course of 7 years also showed a significant improvement of ON/ OFF-fluctuations and dyskinesia [14]. The OFF-times were reduced by 49% (p < 0.001) under LCIG treatment, the duration of dyskinesia by 30% and dyskinesia-related pain by 78%. At the same time, treatment discontinuation rates were low after 7 years with 19% (11 patients). Discontinuation occurred on average 19.3 14.9 months after starting LCIG treatment. LCIG was
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administered for 14.7 0.8 h/d and 72% were treated with LCIG monotherapy at the time of the last examination. After initiation of LCIG treatment, the daily levodopa dose of 1453 372 mg remained practically unchanged at 1506 442 mg over the course of the 7 years (p = 0.204). Use of additional medication was infrequent. Only nine patients received additional dopamine agonists, seven patients were treated with oral levodopa or amantadine and three patients received COMT or MAO inhibitors each. The LCIG treatment led to a reduction of motor complications and improved the independence and global clinical status of 90% of patients. Gait (54%), dysphagia (33%) and dysarthria (18%) also improved sometimes. Furthermore, 44% of patients showed a much improved and 48% of patients a moderately improved quality of life as measured by a 5-point scale. In a recent study of 35 PD patients treated with LCIG, Calandrella et al. identified two main causes of withdrawal: stoma infection (4 patients) and worsening of dyskinesia not manageable with infusion reduction (3 patients) [15]. In another study published by Zibetti et al. all patients who were switched to LCIG treatment reported a positive effect on their sleep behavior, which was reflected by a mean reduction of the Parkinson’s Disease Sleep Scale-2 score by 30.4% [16]. 7. Conclusions Continuous infusion of levodopa/carbidopa via intestinal tube significantly contributes to reducing OFF-times and dyskinesia. This considerably improves the quality of life of patients with advanced PD. Adverse effects observed in the course of LCIG treatment are usually associated with the surgery required for tube placement and generally wear off quickly. The specific adverse effect profile of levodopa/carbidopa is generally comparable with that of oral treatment, apart from significantly less dyskinesia under LCIG therapy. The mean patient age in the four studies described in more detail ranged from 63 to 67 years (Table 1). The positive results indicate that LCIG treatment could be started earlier than currently practiced, e.g., in Switzerland LCIG therapy is generally started at the age of 75 only. LCIG treatment is to be regarded as an alternative to CSAI or deep brain stimulation. However, the decision whether to continue oral treatment with PD medication or to consider a treatment with LCIG, CSAI or DBS should be taken on an individual basis, following consultation with designated specialists for motor disorders.
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Acknowledgments This review has been modified from a non-peer-reviewed article previously published by the same authors for educational purposes in German [7]. Table 1 has been adapted from this article with permission. The authors received an educational grant from AbbVie (Switzerland). References [1] M. Senek, D. Nyholm, Continuous drug delivery in Parkinson’s disease, CNS Drugs 28 (2014) 19–27. [2] D. Nyholm, Duodopa1 treatment for advanced Parkinson’s disease: a review of efficacy and safety, Parkinsonism Relat. Disord. 18 (2012) 916–929. [3] www.rxabbvie.com/pdf/duopa_pi.pdf. [4] www.swissmedicinfo.ch. [5] www.medicines.org.uk/emc/medicine/20786. [6] C.W. Olanow, K. Kieburtz, P. Odin, et al., Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomised, controlled, double-blind, double-dummy study, Lancet Neurol. 13 (2014) 141–149. [7] J.C. Möller, M. Oechsner, Die Rolle der kontinuierlichen jejunalen Infusion von Levodopa/Carbidopa, Leading Opinions Neurol. Psychiatr. 2 (2015) 14–18. [8] J.T. Slevin, H.H. Fernandez, C. Zadikoff, et al., Long-term safety and maintenance of efficacy of levodopa-carbidopa intestinal gel: an open-label extension of the double-blind pivotal study in advanced Parkinson’s disease patients, J Parkinson Dis 5 (2015) 165–174. [9] H.H. Fernandez, D.G. Standaert, R.A. Hauser, et al., Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: final 12-month, open-label results, Mov. Disord. 30 (2015) 500–509. [10] A. Antonini, A. Yegin, C. Preda, et al., Global long-term study on motor and nonmotor symptoms and safety of levodopa-carbidopa intestinal gel in routine care of advanced Parkinson’s disease patients; 12-month interim out-comes, Parkinsonism Relat. Disord. 21 (2015) 231–235. [11] K.R. Chaudhuri, P. Martinez-Martin, R.G. Brown, et al., The metric properties of a novel non-motor symptoms scale for Parkinson’s disease: results from an international pilot study, Mov. Disord. 22 (2007) 1901–1911. [12] A. Antonini, K.R. Chaudhuri, L. Bergmann, A. Yegin, K. Onuk, W. Poewe, Efficacy and safety of levodopa-carbidopa intestinal gel in patients with less than 10 years of Parkinson’s disease – interim results from the GLORIA long-term registry, Mov. Disord. 30 (Suppl. 1) (2015) S67. [13] W. Poewe, K.R. Chaudhuri, L. Bergmann, A. Yegin, S. Dubow, A. Antonini, Global long-term registry on efficacy and safety of levodopa-carbidopa intestinal gel in patients with advanced Parkinson’s disease in routine care (GLORIA) – interim results a in a subgroup of patients with Dyskinesia at Baseline, Mov. Disord. 30 (Suppl. 1) (2015) S112. [14] M. Zibetti, A. Merola, C.A. Artusi, et al., Levodopa/carbidopa intestinal gel infusion in advanced Parkinson’s disease: a 7-year experience, Eur. J. Neurol. 21 (2014) 312–318. [15] D. Calandrella, L.M. Romito, A.E. Elia, et al., Causes of withdrawal of duodenal levodopa infusion in advanced Parkinson disease, Neurology 84 (2015) 1669–1672. [16] M. Zibetti, M. Rizzone, A. Merola, et al., Sleep improvement with levodopa/ carbidopa intestinal gel infusion in Parkinson disease, Acta Neurol. Scand. 127 (2013) e28–e32.
Contents lists available at ScienceDirect
Basal Ganglia journal homepage: www.elsevier.com/locate/baga
New developments in continuous jejunal infusion of levodopa/ carbidopa in advanced Parkinson’s disease Jens Carsten Möller* , Matthias Oechsner Parkinson Center, Center for Neurological Rehabilitation, Hauptstrasse 2-4, 8588 Zihlschlacht, Switzerland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 July 2015 Received in revised form 1 October 2015 Accepted 1 October 2015
Levodopa-associated motor fluctuations and dyskinesia in patients with Parkinson's disease (PD) are often difficult to control by the oral administration of levodopa. Continuous infusion of a levodopa/ carbidopa intestinal gel (LCIG) may represent a feasible treatment option for this patient population. To start LCIG infusion, a temporary nasoduodenal/nasojejunal tube should be considered to show that the patient responds favorably, before a permanent percutaneous endoscopic gastrostomy with jejunal tube (PEG-J) is placed. The present review focuses on recently published key studies on the efficacy and safety of LCIG treatment in advanced PD. The results provide robust evidence of a marked reduction of OFFfluctuations and dyskinesia, thereby also improving the quality of life of these severely disabled patients. LCIG treatment is therefore a promising alternative to continuous subcutaneous apomorphine infusion or deep brain stimulation in advanced PD patients with severe motor fluctuations. ã 2015 Elsevier GmbH. All rights reserved.
Keywords: Duodopa1 Duopa1 Motor complications Non-motor symptoms Quality of life Treatment adherence
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction . . . . . . Olanow et al. [6] . . Slevin et al. [8] . . . . Fernandez et al. [9] Antonini et al. [10] . Other recent studies Conclusions . . . . . . Acknowledgments . References . . . . . . .
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1. Introduction Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder and characterized by the motor symptoms akinesia, rigidity, rest tremor, and postural instability as well as a range of non-motor symptoms. Although the oral symptomatic treatment of motor symptoms in PD has been improved during the previous decades, the gold standard for the therapy of motor symptoms remains levodopa in combination with an inhibitor of aromatic amino acid decarboxylation such as carbidopa. However,
* Corresponding author. E-mail addresses: [email protected] (J.C. Möller), [email protected] (M. Oechsner). http://dx.doi.org/10.1016/j.baga.2015.10.001 2210-5336/ ã 2015 Elsevier GmbH. All rights reserved.
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95 96 96 96 98 98 99 99 99
levodopa-associated motor fluctuations and dyskinesia often pose a major challenge in advanced PD and are difficult to control by the oral administration of levodopa. Alternatives include, e.g., continuous subcutaneous apomorphine infusion (CSAI), deep brain stimulation, and continuous intestinal infusion of levodopa/ carbidopa by means of a gel (LCIG, Duodopa1 in Europe; Duopa1 in the US) [1]. Apart from the continuous drug delivery achieved with LCIG by the direct administration into the small intestine, the stomach passage can be avoided, which may otherwise lead to insufficient active substance absorption due to PD-related irregular gastric emptying [2]. The placement of the intestinal tube (i.e., PEG-J) for LCIG requires surgery with only local anesthesia by most gastroenterology departments. The PEG-J is usually performed after a test phase with a transnasal jejunal tube over several days. Nasal titration is not required in Europe and in the recently issued
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FDA approval for Duopa1, but recommended in Switzerland [3–5]. Duodopa1/Duopa1 is indicated for the treatment of advanced levodopa/responsive PD with severe motor fluctuations and hyper-/dyskinesia when available combinations of Parkinson medicinal products have not given satisfactory results. The present review focuses on new developments with respect to LCIG infusion in advanced PD with special emphasis on four recently published clinical trials. 2. Olanow et al. [6] The randomized, double-blind, double-dummy, double-titration HORIZON study included 71 patients with advanced PD, who did not achieve satisfactory control of OFF-times with optimized drug therapy (oral levodopa/carbidopa, dopamine agonist and at least one other PD medication) (Table 1) [6]. Participants received stable doses of levodopa for at least 4 weeks before enrolment in the study and had at least 3 h of OFF-time per day as measured by a home diary. Subjects receiving sustained-release levodopa/carbidopa, Stalevo1 (Orion Pharma, Finland), or other formulations of levodopa were permitted after conversion to equivalent doses of immediate-release levodopa/carbidopa at least 4 weeks before study entry. Additional PD medication was permitted, provided that its dosage had remained stable for 4 weeks prior to randomization and no dose adjustments were made during the study. Subjects were randomized to treatment with LCIG plus oral placebo or to oral levodopa/carbidopa plus placebo intestinal gel. Compared to baseline, the mean daily OFF-time as primary outcome measure was reduced by 4.04 h/d (standard error [SE] 0.65) in the LCIG group and by 2.14 h/d (SE 0.66) in the placebo group. This difference was highly significant in favor of LCIG treatment (p = 0.0015). At the same time, ON-time without troublesome dyskinesia as secondary outcome measure was increased in the LCIG group by 4.11 h/d (SE 0.75) vs. 2.24 h/d (SE 0.76) in the placebo group (p = 0.0059). The Parkinson Disease Questionnaire-39 (PDQ-39) Summary Index values were reduced as compared to the baseline value by 10.9 points (SE 3.3) in the LCIG group and by 3.9 points (SE 3.2) in the placebo group (p = 0.0155). Furthermore, the mean score on the Clinical Global Impression-Improvement (CGI-I) scale (7-point scale from 1 = very much improved to 7 = very much worse) was 2.3 points (SE 0.4) in the LCIG group and 3.0 points (SE 0.4) in the placebo group at the final examination (p = 0.026). Although almost all study subjects experienced adverse effects (95% in the LCIG group, 100% in the placebo group), that occurred mainly as a result of the tube placement, most were temporary and limited to the first week following PEG-J tube placement. Four of the 71 patients showed signs of polyneuropathy (1 in the LCIG group, 3 in the placebo group). No cases of Guillain-Barré syndrome were observed [6]. 3. Slevin et al. [8] In contrast to the HORIZON study design, in which no dose adjustments were permitted after the titration phase, continuous adjustment of the LCIG dose is standard practice in Europe. This practice corresponds to the protocol of the 1-year, open-label HORIZON extension study published by Slevin et al. [8] (Table 1). Prior to a new titration phase, the LCIG-naive group that received placebo during the HORIZON study was switched to LCIG. Due to tapering of the other PD medication and the continuous LCIG dose adjustment, 65% of all patients were treated with a levodopa monotherapy consisting of LCIG with or without oral levodopa during the night at the end of the study. In the LCIG-naive patients, start of LCIG infusion led to a mean OFF-time reduction of 2.34 h/d (SD 2.78; p < 0.001) starting from BL 5.08 h/d (SD 2.03), while in
the LCIG-treated group (patients treated with LCIG during the HORIZON study), continuation of LCIG resulted in a moderate mean reduction from BL 3.11 h/d (SD 2.56) of 0.42 h/d (SD 2.67; p = 0.377). Interestingly, the combined effect on OFF-time in the pivotal trial plus extension was the same for both groups irrespective of early versus later start of LCIG-treatment. During both consecutive studies, OFF-time with 6.3 h/d (SD 1.7) at BL decreased 4.04 h/d (SE 0.65) and 0.42 h/d (SD 2.67) in the LCIGgroup versus the LCIG-naïve group where OFF-time with 7.0 h/d (SD 2.1) at BL decreased 2.14 h/d (SE 0.66) and 2.34 h/d (2.78), respectively. The mean increase of ON-time without troublesome dyskinesia was 2.19 h/d (SD 3.7; p = 0.005) in the LCIG-naive and 1.0 h/d (SD 2.58; p = 0.036) in the LCIG-treated group. The improvement in the LCIG-treated group is possibly explained by the fact that the LCIG dose was optimized at the start of the extension study and that dose adjustments were now permitted throughout the entire study duration (Table 1). No significant changes to quality of life were observed during the extension study. However, the CGI-I score showed significant improvement in both groups (by 2 points each; p < 0.001) and the majority of patients improved very much (40%), much (>27%) or minimally (>13%). It was possible to assess the safety of LCIG independently of complications caused by the tube placement, as the duodenal tube had already been placed during the HORIZON study, 12 weeks prior to the start of the extension study [6]. With regard to the incidence of potential levodopa-associated adverse effects such as dyskinesia, hallucinations and orthostatic hypotension, no difference was observed between the LCIG-treated and LCIG-naive groups during the first 4 weeks. 77% of patients experienced adverse effects possibly or probably related to the treatment. However, these were generally mild to moderate. The incidence of adverse effects continuously decreased over the course of the study duration (from 52% to 24%, evaluation every 30 days). The most common serious adverse effects were complications associated with the tube placement (5%), abdominal pain (3%), asthenia (3%) and pneumonia (3%). A not severe polyneuropathy was observed in 9.7% of patients (3 LCIG-naive, 3 LCIG-treated), which is within the normal rates of polyneuropathy in PD [8]. Treatment adherence was high at 89% over the course of a year. 4. Fernandez et al. [9] The study design of the largest prospective open-label LCIG study (n = 354) by Fernandez et al. reflects standard procedure in Europe (Table 1) [9]. In this study, the initial LCIG monotherapy dosage was determined via nasal titration. Additional PD medication was only permitted after subsequent dose titration (in this case, 28 days after PEG-J placement) and dose adjustments were permitted throughout the entire study duration. The final data confirm the results of the HORIZON study. The mean daily OFFtime was reduced by 65.6%, i.e., by 4.4 h/d (SD 2.9; p < 0.001), and the ON-time without troublesome dyskinesia increased by 62.9%, i.e., by 4.8 h/d (SD 3.4; p < 0.001). These improvements persisted throughout the entire treatment duration of 54 weeks. Furthermore, the CGI-I score showed that 22.4% of patients were very much improved, 55.5% were much improved and 13.7% were minimally improved. 3.1% of patients showed no change; 2.8% reported to be minimally worse and 1.0% to be much worse. The mean PDQ-39 Summary Index was 6.9 14.1 points lower than the baseline value. A statistically significant mean improvement was achieved in seven of the eight PDQ-39 dimensions, social support being the only exception [9]. It should also be noted that the daily dose remained stable after initial nasal titration (mean LCIG dose of 1572 mg/d at last visit), which indicates that no obvious LCIG
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97
Table 1 Study overview on LCIG (with permission from [7])
Patients included Inclusion criteria
Olanow et al. [6] HORIZON Pivotal Study
Slevin et al. [8] HORIZON extension study
Fernandez et al. [9] Open-label 12-month study
Antonini et al. [10] GLORIA 24-month study: 12-month interim analysis
n = 71
n = 62
n = 354
n = 172 Patients with advanced PD eligible for LCIG treatment according to local SPC and national reimbursement criteria
Positive response to levodopa Diagnosis according to UK Parkinson’s Disease Society Brain Bank criteria Severe motor fluctuations defined as 3 h/d OFF-time during baseline despite optimized oral PD treatment
Study design
Switch to immediate-release levodopa/carbidopa Tube placement Randomization to study arms: LCIG plus oral placebo or oral immediaterelease levodopa/carbidopa plus intestinal placebo gel Titration over the course of 4 weeks Overall study duration 12 weeks No LCIG dosage adjustment possible after titration Stable dosage of oral PD comedication during study
New adjustment of LCIG dose in LCIG-naive and LCIG-treated patients Initial dose according to optimized oral levodopa/carbidopa dose prior to randomization to the double-blind HORIZON study Titration for 1 week LCIG treatment over the course of 52 weeks LCIG dosage adjustment possible after titration Tapering of oral PD comedication possible during study
Nasojejunal titration 2–14 days LCIG titration 2–14 days LCIG treatment over the course of 54 weeks Individual dose adjustments possible during study Gradual introduction of oral PD comedication only permitted 28 days after PEG-J placement Oral immediate release levodopa/carbidopa only permitted during the night Apomorphine and controlledrelease levodopa/carbidopa not permitted
LCIG-naive patients Start of LCIG infusion by temporary nasoduodenal tube to test clinical response and perform titration of LCIG Dose should be adjusted to an optimal clinical response for each patient, which means maximizing the functional ONtime during the day by minimizing the OFF-time and ONtime with disabling dyskinesia. PEG-J placement and treatment with permanent tube over the course of 24 months Results presented from the 12month interim analysis
Mean age at baseline (years) Mean OFFtime (h/d) at BL Mean reduction of OFF-time (h/ d)
LCIG: 63.7 [SE 9.5] Placebo: 65.1 [SE 6.8]
LCIG-treated: 63.6 [SD 9.0] LCIG-naive: 64.8 [SD 6.6]
64.1 [SD 9.1]
66.5 [SD 9.3]
LCIG: 6.3 [SE 1.7] Placebo: 7.0 [SE 2.1]
LCIG-treated: 3.11 [SD 2.56] LCIG-naive: 5.08 [SD 2.03]
6.75 [SD 2.35]
7.1 [SD 3.5]
LCIG: 4.04 [SE 0.65] Placebo: 2.14 [SE 0.66]
LCIG-treated: 0.42 [SD 2.67; p=0.377] LCIG-naive: 2.34 [SD 2.78; p<0.001]
4.4 [SD 2.9; p < 0.001]
4.7 [SD 3.4; p < 0.0001]
LCIG: 8.7 [SE 2.0] Placebo: 7.8 [SE 2.5]
LCIG-treated: 11.83 [SD 2.68] LCIG-naive: 9.86 [SD 2.61]
7.65 [SD 2.45]
NA
LCIG: 4.11 [SE 0.75] Placebo: 2.24 [SE 0.76]
LCIG-treated: 1.00 [SD 2.58; p = 0.036] LCIG-naive: 2.19 [SD 3.7; p = 0.005]
4.8 [SD 3.4; p < 0.001]
NA
NA
NA
NA
5.2 [SD 4.5]
NA
NA
NA
1.7 [SD 5.0; p = 0.0228]
NA
NA
NA
75.3 [SD 42.2]
NA
NA
NA
22.2 [SD 50.6; p = 0.0014]
PDQ-39
PDQ-39
PDQ-39
PDQ-8
35.1 [SD 18.0]
LCIG-treated: 22.0 [SD 17.1] LCIG-naive: 32.1 [SD 17.2]
42.8 [SD 15.1]
48.6 [SD 19.0]
PDQ-39
PDQ-39
PDQ-39
PDQ-8
10.9 [SE 3.3; p = 0.0155]
LCIG-treated: sustained improvement
6.9 [SD 14.1 p<0.0001]
8.6 [SD 22.6; p=0.0100]
Mean ON-time without troublesome dyskinesia (h/d) at BL Mean increase of ON-time without troublesome dyskinesia (h/d) Mean ON-time with disabling dyskinesia (h/d) at BL Mean reduction of ON-time with disabling dyskinesia (h/d) NMSS Score at BL Mean reduction of NMSS Score Quality of Life: PDQ-8/39 Score at BL Mean reduction of PDQ-8/39 Score
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Table 1 (Continued) Olanow et al. [6] HORIZON Pivotal Study
Slevin et al. [8] HORIZON extension study
Fernandez et al. [9] Open-label 12-month study
Antonini et al. [10] GLORIA 24-month study: 12-month interim analysis
EQ-5D
EQ-5D
SI Score: 0.588 [SD 0.195] VAS Score: 50.2 [SD 21.0]
SI Score: 0.39 [SD 0.311] VAS Score: 47.3 [SD 20.9]
EQ-5D
EQ-5D
SI Score: 0.064 [SD 0.203; p < 0.0001] VAS Score: 14.0 [SD 24.8; p < 0.0001]
SI Score: 0.12 [SD 0.35; p = 0.0076] VAS Score: 15.6 [SD 24.7; p = 0.0001]
LCIG-naive: no significant improvement Quality of Life: EQ-5D Summary Index and VAS Score at BL Mean increase of EQ-5D Summary Index and VAS score
EQ-5D
NA
BL results not shown
EQ-5D
NA
LCIG: ns Placebo: ns
tolerance development took place. Administration rates of other PD medication were low and 76.5% of patients stayed on levodopa/ carbidopa monotherapy. Adverse effects were observed in 46.9% of patients during nasal titration. The most common adverse effects were insomnia (7.9%) and nasojejunal tube placement complications (7.3%) as well as oropharyngeal pain (6.5%). After conclusion of nasal titration, adverse effects were observed in 92% of patients receiving LCIG during the PEG-J phase. These were generally mild to moderate and transitory. Most common were tube placement complications (34.9%), pain during and after surgery (20.7%) and abdominal pain (31.2%) [9]. 5. Antonini et al. [10] The first interim data after a 12-month treatment duration of the international postmarketing surveillance study for Duodopa1 (GLORIA; n = 172) were published in early 2015 [10]. Patients were treated in accordance with the country-specific marketing authorization, whereby the LCIG dose was determined by the treating study physician and adjusted individually for each patient over the course of the study. The few exclusion criteria and the flexible dosage give the study practical relevance. After 12 months of treatment with LCIG, the daily OFF-time was reduced by 4.7 h/d (SD 3.4; p < 0.0001) and the ON-time with dyskinesia was reduced by 1.7 h/d (SD 5.0; p = 0.0228) as compared to baseline (Table 1). Severity coded of disabling Dyskinesia (UPDRS item 33) was reduced from 1.7 (SD 1.2) at BL to 0.9 (SD 1.2; p < 0.0001) and painful dyskinesia (UPDRS item 34) was reduced from 0.8 (SD 1.1) to 0.6 (SD 1.2; p = 0.0004). Non-motor symptoms (NMS) in PD are common and significantly reduce quality of life. One validated clinical tool to assess the progress or potential response to treatment of NMS had been developed with nine dimensions: cardiovascular, sleep/fatigue, mood/cognition, perceptual problems, attention/memory, gastrointestinal, urinary, sexual function, and miscellany [11]. The NMSS score diminished from 75.3 (SD 42.2) at BL by 22.2 points (SD 50.6; p = 0.0014), and improvements of non-motor symptoms were observed in 3 out of 9 NMSS domains to month 12, i.e., “Sleep/ Fatigue” (p = 0.0001), “Gastrointestinal tract” (p = 0.0096) and “Urinary” (p = 0.0199), while improvements in “Mood/Cognition” were evident to month 6 (p = 0.0426). PDQ-8 score improved by 8.6 (SD 22.6; p = 0.0100), and improvements of QoL were observed in 3 out of 8 PDQ-8 items to month 12, i.e., “Difficulty getting around in public places” (p = 0.0074), “Felt depressed” (p = 0.0372), and “Embarrassed by having PD” (p = 0.0312), while improvements in “Painful muscle cramps and pains” were evident to month 6
(p = 0.0031). The EQ-5D VAS Score improved to month 12 (p = 0.0001) and enhancement in the summary index score was evident to month 6 (p = 0.0076). The adverse effect profile was comparable to the results of other studies [10]. Results of two subgroup analysis from GLORIA performed with the interim data were presented at the 19th Annual International Congress of Parkinson’s Disease and Movement Disorders in June 2015 in San Diego: A.) Patients younger than 60 years old and with less than 10 years of Parkinson’s disease [12]: At BL, patients in this subgroup had a mean age of 52.5 (SD 5.7; n = 28) years and 6.1 (SD 1.9) years disease duration. OFF-time (8.0 h/d; SD 3.3) was longer and NMSS score was higher (76.3; SD 40.3) relative to the total population. After 12 months of LCIG treatment, the daily OFFtime was reduced by 6.7 h/d (SD 2.2; p < 0.0001) and the NMSS score by 32.9 points (SD 46.5; p < 0.05). In conclusion, LCIG treatment in younger patients with a relatively early disease stage resulted in a marked decrease of OFF-time and nonmotor symptoms comparable to the entire population (n = 343; age: 66.7, SD 8.4; disease duration: 12.8, SD 6.2). B.) Patients with >4 h/d dyskinesia [13]: The reduction from total time with dyskinesia at BL (7.2 h/d; SD 2.9; n = 114) was 3.0 h/d (SD 8.6; p = 0.0017) at month 12 (n = 86) and 3.0 (SD 5.9; p = 0.0339) at month 24 (n = 20). Duration of dyskinesia was reduced by more than 2 h/d in 69% of patients at month 12 and in 60% of patients at month 24. The reduction from PDQ-8 total score at BL (48.8; SD 19.6) was 16.6 (SD 24.2; p < 0.0001) at month 12 (n = 67) and 9.6 (SD 22.8; p = 0.1144) at month 24 (n = 16). In conclusion, advanced PD patients with pronounced dyskinesia at BL had a significant and long-term improvement in dyskinesia during LCIG treatment. The observed ADR profile in both subgroups was consistent with the established safety profile of LCIG [12,13]. 6. Other recent studies The prospective long-term data (n = 59) obtained over the course of 7 years also showed a significant improvement of ON/ OFF-fluctuations and dyskinesia [14]. The OFF-times were reduced by 49% (p < 0.001) under LCIG treatment, the duration of dyskinesia by 30% and dyskinesia-related pain by 78%. At the same time, treatment discontinuation rates were low after 7 years with 19% (11 patients). Discontinuation occurred on average 19.3 14.9 months after starting LCIG treatment. LCIG was
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administered for 14.7 0.8 h/d and 72% were treated with LCIG monotherapy at the time of the last examination. After initiation of LCIG treatment, the daily levodopa dose of 1453 372 mg remained practically unchanged at 1506 442 mg over the course of the 7 years (p = 0.204). Use of additional medication was infrequent. Only nine patients received additional dopamine agonists, seven patients were treated with oral levodopa or amantadine and three patients received COMT or MAO inhibitors each. The LCIG treatment led to a reduction of motor complications and improved the independence and global clinical status of 90% of patients. Gait (54%), dysphagia (33%) and dysarthria (18%) also improved sometimes. Furthermore, 44% of patients showed a much improved and 48% of patients a moderately improved quality of life as measured by a 5-point scale. In a recent study of 35 PD patients treated with LCIG, Calandrella et al. identified two main causes of withdrawal: stoma infection (4 patients) and worsening of dyskinesia not manageable with infusion reduction (3 patients) [15]. In another study published by Zibetti et al. all patients who were switched to LCIG treatment reported a positive effect on their sleep behavior, which was reflected by a mean reduction of the Parkinson’s Disease Sleep Scale-2 score by 30.4% [16]. 7. Conclusions Continuous infusion of levodopa/carbidopa via intestinal tube significantly contributes to reducing OFF-times and dyskinesia. This considerably improves the quality of life of patients with advanced PD. Adverse effects observed in the course of LCIG treatment are usually associated with the surgery required for tube placement and generally wear off quickly. The specific adverse effect profile of levodopa/carbidopa is generally comparable with that of oral treatment, apart from significantly less dyskinesia under LCIG therapy. The mean patient age in the four studies described in more detail ranged from 63 to 67 years (Table 1). The positive results indicate that LCIG treatment could be started earlier than currently practiced, e.g., in Switzerland LCIG therapy is generally started at the age of 75 only. LCIG treatment is to be regarded as an alternative to CSAI or deep brain stimulation. However, the decision whether to continue oral treatment with PD medication or to consider a treatment with LCIG, CSAI or DBS should be taken on an individual basis, following consultation with designated specialists for motor disorders.
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