Long‐term safety and effectiveness of levodopa‐carbidopa intestinal gel infusion

Abstract Introduction Levodopa‐carbidopa intestinal gel (LCIG) infusion has demonstrated to improve motor fluctuations. The aim of this study is to assess the long‐term safety and effectiveness of LCIG infusion in advanced Parkinson's disease (PD) patients with motor fluctuations and its effect in nonmotor symptoms. Methods Adverse events (AE) and their management, clinical motor, and nonmotor aspects were assessed up to 10 years. Thirty‐seven patients were treated with LGIC; in three subsets of patients, specific batteries of tests were used to assess cognitive and behavior assessment for 6 months, quality of sleep for 6 months, and quality of life and caregiver burden for 1 year. Results There was a high number of AE, but manageable, most of mild and moderate severity. All patients experienced significant improvement in motor fluctuations with a reduction in mean daily off time of 4.87 hr after 3 months (n = 37) to 6.25 hr after 9 years (n = 2). Diskynesias remained stables in 28 patients (75.7%) and improved in 5 patients (13.5%). There was no neuropsychological deterioration, but an improvement in attentional functions, voluntary motor control, and semantic fluency. Quality of sleep did not worsen, and there was an improvement in the subjective parameters, although overnight polysomnography did not change. There was a significant sustained improvement of 37% in PD‐Q39 after 3 months and to 1 year, and a significant reduction in caregiver burden of 10% after 3 months. Conclusion LCIG infusion is a safe and efficacious treatment for the control of motor fluctuations, and for improvement or nonworsening of nonmotor aspects, long‐term sustained, and feasible for use in routine care.


| INTRODUCTION
A group of treated patients experience motor complications (fluctuations and dyskinesias) when Parkinson's disease (PD) progresses. At this stage of the disease, there are three "second line" device-aided therapeutic options which may be offered to patients: deep brain stimulation (DBS), subcutaneous infusion of apomorphine (SIApo), and continuous intrajejunal infusion of levodopa-carbidopa intestinal gel (LCIG) (Martínez-Martin et al., 2015;Munro Neville, Parsons, Askmark, & Nyholm, 2012).
Optimizing levodopa delivery with LCIG infusion is a treatment option for advanced PD with 10 years in the European market. LCIG infusion has demonstrated to improve motor fluctuations by reducing fluctuations in plasma levodopa levels. The effect of LCIG in other settings has been poorly studied. Some works have demonstrated that treatment with LCIG may improve nonmotor symptoms of PD, may improve cognitive function and behavior (Sanchez-Castañeda et al., 2009;Zibetti et al., 2013), quality of sleep in these patients (Eggert et al., 2008;Honig et al., 2009), and patient's quality of life (QoL) and caregiver burden (Isacson, Bingefors, Kristiansen, & Nyholm, 2008;Puente et al., 2010;Santos-García et al., 2012). However, LCIG is a complex and expensive treatment and data on long-term standard clinical practice therapy complications and their management are scarce.
There is still little known about long-term follow-up of LGIC infusion in PD patients. There are only two other 10-and 17-year retrospective studies (Nyholm, Johansson, Lennernäs, & Askmark, 2012;Nyholm et al., 2008), and one 10-year prospective study (Lim, Schoeman, & Nguyen, 2015). However, the 10-year prospective study only include follow-up of the percutaneous endoscopic gastrostomy (PEG) procedure.
The aim of this study is to analyze our long-term experience in the management of LCIG treatment for PD with motor fluctuations, the safety and effectiveness of this therapy in the control of motor fluctuations, and its effect in other motor and nonmotor symptoms, such as cognitive and sleep disorders, impact in their QoL and caregiver burden, problems found and actions taken to solve them, and reason for treatment discontinuation.

| Study design and patient selection
This was a long-term, open-label, prospective, observational study in 37 patients with advanced PD, responders to levodopa, and with disabling motor fluctuations. All patients included fulfilled the UK Brain Bank criteria (Hughes, Daniel, Kilford, & Lees, 1992) for the diagnosis of idiopathic PD and were experiencing severe motor fluctuations, which were debilitating in daily life, despite receiving optimized conventional oral medications. Patients had been previously treated with oral levodopa combined with entacapone, rasagiline, dopamine agonists, and/or apomorphine injections, 9 of them presented adverse events (AEs) with SIApo and 4 were dismissed for DBS. Patients with atypical parkinsonian features were not included (Wenning et al., 2000).
All PD medication was switched to LCIG (Duodopa ® AbbVie) at the start of study treatment. LCIG was initially administered as a continuous duodenal infusion via a nasoduodenal probe using a portable external pump in order to assess individual treatment response and required dose during a test period of 3-10 days (4 days in average).
A gastroduodenal catheter was then introduced by PEG for permanent infusion of perfused LCIG. Levodopa-carbidopa was supplied by the same portable pump via a catheter into the jejunum, with dose delivery individually adjusted to minimize Off time periods and dyski- Three open-label, prospective, observational substudies were carried out in three groups of patients from this population of patients with advanced PD: Nonmotor assessment of cognition and behavior (Substudy 1), nonmotor effects on quality of sleep (Substudy 2), and assessment of health status, QoL, and caregiver burden (Substudy 3).
The study was conducted in compliance with the ethical standards and was approved by the Ethics Committee of the institution (Vall d'Hebron University Hospital), and followed the Spanish Law 15/1999 on Personal Character Data Protection concerning confidentiality of Patient's data. All patients participating in the study signed the corresponding written consent form.

| Clinical evaluation/assessments
The following parameters were analyzed prior to LCIG treatment (at baseline), at months one, three, six, and twelve, and every year after-  • Visual-constructional visuospatial and visuoperceptual functions: Clock Drawing Test-(order and copy)-visual-constructional; Reading clocks-simple visuospatial ability; and Luria test of overlapping figures-visual perceptive skills function.
• Memory and learning: Rey Auditory-Verbal Learning Test (RAVLT)-Short-and long-term audio-verbal memory and recognition.
• Language: Boston Naming Test (BNT)-Title by visual comparison.  Hamilton anxiety scale, administered prior to treatment (at baseline) and 6 months after treatment. In addition, an overnight polysomnography (PSG) study was carried out at these timings.

| Statistical analysis
Statistical analysis was carried out using the SPSS statistical package v17.0 for Windows. A p value <.05 was considered statistically significant.
Variables were expressed as frequency (percentages)

| Baseline characteristics and LCIG treatment administration
Thirty-seven patients were included (22 males, 15 females) to treatment with LCIG. The mean age was 68.2 ± 6.8 years (57-80) and the mean duration of the disease was of 13.5 ± 5.6 years (5-26).

| Safety assessment
Patients presented a high number of AEs, mainly related to the device and the infusion system, but also to the PEG procedure and the gastrostomy as well as to the treatment, with a similar profile as described for oral levodopa (Table 1).
Most of the AEs were of mild and moderate severity, and serious in a minor degree. Serious complications related to PEG procedures and gastrostomy were 1 stoma dermatitis and 3 stoma infection; 4 PEG removal and 3 PEG hooked related to infusion device; and 1 leg pain, 1 polyneuropathy (PNP), 2 freezing in On, 3 dyskinesia, and 3 weight loss related to LCIG treatment.
Although treatment was temporary discontinued as a consequence of some of these AEs, they were manageable and actions taken allowed continuing treatment in most cases (

| Effectiveness assessment
After LCIG treatment, all patients showed a significant and sustained motor improvement in motor fluctuations (Figure 2), with a reduction in daily mean Off time of 4.9 ± 1.1 hr after 3 months (p < .001) in 37 patients, 4.9 ± 1.1 after 2 years (p < .001) in 23 patients, 5.0 ± 1.1

| Substudy 1-Cognition and behavior assessment
This substudy included five patients (three males, two females) with a mean age of 69.6 (60-73) years and a mean disease duration of 14.4 (8-22) years.
No statistical significant differences were found between baseline scores and after 6 months of treatment in any of the neuropsychological tests, despite most scores tend to be maintained or improved in some tests. After LCIG there was an improvement of 5 points in verbal memory, short-and long-term attentional functions, voluntary motor control, phonetic verbal fluency, and naming (Table 2). Regarding behavior, no differences between assessments were found. Stroop-word color errors 0.7 ± 0.9 3.0 ± 3.6 .357
(8-15) years. Before starting treatment with LCIG, the quality of sleep was bad either in objective and subjective parameters (Table 3) PSG showed a low efficiency of sleep in these PD patients. No significant differences were found in the macrostructure of sleep, respiratory events, and PLMs after 6 months of treatment (Table 3).
The subjective questionnaire on somnolence showed that patients with somnolence improved after treatment, although not significantly. There was an improvement of 5 points in the Epworth scale without deterioration of the subjective parameters of quality of sleep, depression, fatigue, anxiety, or objective parameters of overnight PSG.

| Substudy 3-QoL and caregiver burden
This substudy included nine patients (eight males, one female) with a mean age of 69.6 (57-78) years and a mean disease duration of 14.4 (8-23) years.
There was a significant global clinical improvement, improvement of QoL and health status, and lower healthcare burden after treatment with LCIG (Table 4). There was a sustained improvement in PD-Q39 questionnaire of 37% at 3, 6, and 12 months with a mean decrease of 21 points (p < .05). EQ-5D questionnaire significantly improved at 1 week and at 3 and 12 months with a mean decrease of 2 points (improvement of 20%, p < .05). EQ-VAS scale was significantly better at 1 week and at 3 months with an increase of 14 points (improvement of 25%, p < .05). The caregiver burden evaluated by ZBI significantly improved a 20% at 3 months with a mean decrease of 8.7 points (p = .042), being the improvement lower and nonsignificant after 1 year (10% improvement with a mean decrease of 3.2 points).

| DISCUSSION
This is the first and longest follow-up prospective study carried out in Spain on long-term effects of LGIC infusion in PD patients.
Our safety profile was consistent with previous studies (Cáceres-Redondo et al., 2014;Nyholm et al., 2008;Zibetti et al., 2014). The most frequent issues in our study were related to the infusion device and mainly of mild intensity, although we also found serious complications such as PEG removal in four patients and PEG hooked in three patients. Most of these complications were preventable with annual/ biennial PEG replacement. Complications related to PEG procedures and gastrostomy were also frequent and generally mild, although there also were serious issues such as stoma dermatitis in one patient and stoma infection in three patients. All complications were solved with topical/systemic treatment, and only in one patient lead to treatment permanent discontinuation (this same patient presented PEG hooked, and has a deficient hygiene and progressive dementia).
With regard to AEs related to treatment, there were 13 patients with PNP, four cases already present prior to treatment, four cases of small fiber PNP, four cases of axonal subacute PNP, and one case of serious acute axonal PNP. Almost all cases evolved to stabilization or improvement except the acute PNP case who was stabilized but with neurologic sequelae. Presence of PNP was already described with long-term treatment at high doses of oral levodopa (Puente et al., 2010), present either as Guillain-Barré syndrome (Antonini et al., 2007), or as axonal PNP in the context of vitamin B12 deficit or other group B vitamins (Manca et al., 2009;Santos-García et al., 2010 Results in mean ± standard deviation. N, Sleep stages; AHI, Apnea Hypopnea Index; PLM, periodic leg movement; CT90, oxygen saturation below 90%. *p < .05 indicate significant differences compared to baseline.
Despite the complexity of the treatment and the high number of AEs occurred, as most AEs were manageable and with the good effectiveness results found, LGIC treatment may be maintained over a period of 10 years so far. In fact, in our study LGIC treatment has been used as rescue treatment for nine patients previously receiving SIApo and four previously receiving DBS, while within patients receiving LGIC only one received rescue treatment with SIApo and one with DBS.
Several studies have shown the effectiveness of LCIG therapy in motor and nonmotor fluctuations in the standard clinical practice in PD (Buongiorno et al., 2015;Eggert et al., 2008;Fernandez et al., 2015). In our study, a significant reduction in mean daily Off time of 4.8 hr was found in all patients after LCIG treatment, which is slightly higher than the reduction in mean daily Off time of 4.4 hr found in a 12-month study , and of 4 hr in a 12-week follow-up study (Olanow et al., 2014). Our slightly higher results are probably because the standard clinical practice allows greater agility and versatility in the treatment.
Improvement of dyskinesias with long-term treatment with LCIG has been confirmed in several studies up to 7 years with significant reductions in On time during waking time without incapacitating dyskinesias (Antonini et al., 2013;Santos-García et al., 2010), and global improvement of dyskinesias (Cáceres-Redondo et al., 2014;Olanow et al., 2014;Timpka et al., 2016;Zibetti et al., 2014), while other studies did not confirm this results  or reported clinical worsening of patients in a short series of patients (Raudino et al., 2009). In our study the percentage of waking time with dyskinesias was reduced in six patients and maintained in the remaining 31 patients, and severity of dyskinesias improved in five patients, remaining stable in 28, but worsening in four being a reason for withdrawal in one of them.
Furthermore, our study found a significant improvement in motor stages measured with H&Y and motor functions independence and the ability to perform daily activities measured by S&E scale at midterm.
Our study is not designed to compare the progressive motor deterioration of natural disease evolution, and therefore we compare with the same population prior to treatment and at midterm (3 months).
In line with precedent studies (Eggert et al., 2008;Honig et al., 2009) we also found significant improvement of nonmotor symptoms, particularly those concerning cognitive and behavior function assessed with UPDRS part I. The Non-Motor Symptoms Assessment Scale for Parkinson's disease was not used because it was not yet validated before the start of our prospective study.
In our experience, nonmotor neuropsychiatric disorders, which are frequent in this population, persisted with treatment but did not worsen in general. Impulse control disorders improved and there was not a single new case occurring. A similar experience was recently found in a 6-month prospective study (Catalán et al., 2013) and in a 3- year prospective study (Todorova, Samuel, Brown, & Chaudhuri, 2015 Results in mean ± standard deviation. PDQ-39, quality-of-life questionnaire in PD-39 items; EQ-5D, European Quality of life-5 dimensions; EQ-VAS, European quality-of-life Visual Analogue Scale; ZBI, Zarit Burden Index. *p < .05 indicate significant differences compared to baseline. The effectiveness of the treatment was also evidenced with a significant global clinical improvement, a significant improvement in their QoL and health status, and lower caregiver burden. LCIG significantly improved a 26% the QoL assessed by PDQ-39. We obtained similar results than other studies with follow-up periods up to 2 years (Antonini et al., 2008(Antonini et al., , 2013Fasano et al., 2012;Fernandez et al., 2015;Santos-García et al., 2012;Slevin et al., 2015). Neurodegenerative diseases, such as PD, have a considerable social burden, particularly for the caregiver. In our study LCIG treatment reduced in a 20% the caregiver burden at midterm (3 months) and a 10% at long term (1 year).
Although the statistical potency was low due to the small sample size, there were no evidences that patients undergoing this treatment, despite the limitations and complications, had worse QoL or worse caregiver burden. Results from other studies found a tendency toward an improvement in caregiver burden with LCIG treatment (Cáceres-Redondo et al., 2014;Fasano et al., 2012;Olanow et al., 2014;Sensi et al., 2014;Slevin et al., 2015).
The safety and effectiveness results are particularly important due to the long-term prospective follow-up, leading to a better knowledge of LCIG therapy in all aspects, both motor and nonmotor, and on its complications. This is the major strength of this study. The study provides valuable information obtained in the standard clinical practice conditions, and will help to optimize treatment for patients currently receiving or who will receive in the future LCIG treatment. One important limitation in this study is the small sample size in some of the substudies, which determines a low statistical power in the comparisons. Therefore, the results found should be interpreted with caution.
LCIG may be considered a complex treatment strategy for advanced PD with motor fluctuations where drug combinations currently available did not provide satisfactory results. Considering the high cost of LCIG treatment, the potential serious AEs, and their complexity, the most likely candidates for this treatment should be identified and a multidisciplinary specialized and protocolized management is recommended together with the patient cooperation and his/her caregiver or assistant support.
Our longest follow-up prospective study confirms that LGIC treatment is an efficacious treatment for the control of motor fluctuations, and for improvement or nonworsening of other motor and nonmotor aspects of PD, being well tolerated and safe, long-term sustained, and feasible for use in the standard clinical practice.