Abstract
Background
Levodopa–entacapone–carbidopa intestinal gel (LECIG) was introduced on the Swedish market in 2019. The therapy is aimed at patients with Parkinson's disease (PD) with fluctuations and dyskinesias. Long‐term efficacy and safety data are lacking.
Objective
To investigate the efficacy, tolerability, and safety of LECIG in regular clinical practice for Parkinson's disease in Sweden.
Methods
Real‐world data were collected from the Swedish registry for Parkinson's disease (ParkReg) for all patients reported to receive LECIG during the period from 2019 until 31 August 2022.
Results
A total of 150 patients were identified. Sixty‐one (41%) of 150 patients were females. At the start of treatment, the median age was 73 years (range: 43–86). The median duration since motor symptoms onset was 17 years (IQR: 9). Fifty (33%) of 150 patients switched from another device‐assisted therapy, mostly LCIG (39 patients).
Reported complications were mainly related to PEG‐J tube and stoma (30%). Twenty (13.3%) of 150 patients discontinued LECIG and 11 (7.3%) patients died while on LECIG.
The Parkinson KinetiGraph scores for bradykinesia, dyskinesia, fluctuations, tremor, and immobility for 53 patients during LECIG showed good therapy control. The median (IQR) p‐Hcy during LECIG was 12 (4.6) μmol/L (n = 44). The median (IQR) PDQ‐8 summary index during LECIG was 31 (17) (n = 52). The median (IQR) EQ5D during LECIG was 0.62 (0.32) (n = 41).
Conclusions
Data from ParkReg covering 150 patients over 3 years show LECIG to be an effective and safe device‐aided therapy for advanced PD. However, the long‐term efficacy and tolerability of LECIG need to be further investigated.
Keywords: levodopa, Parkinson's disease, registries, Sweden
INTRODUCTION
Motor fluctuations and dyskinesias are common complications of oral dopaminergic therapy in most patients as Parkinson's disease (PD) progresses [1]. Motor and nonmotor fluctuations have a significant negative impact on patients [2, 3], their caregivers' quality of life [4, 5], and healthcare system resources [6, 7, 8]. Device‐aided therapy (DAT) with continuous drug delivery or continuous high‐frequency deep brain stimulation (DBS) reduces the occurrence of both motor fluctuations and dyskinesias [9, 10, 11]. Both DBS and device‐aided continuous drug delivery, such as levodopa‐carbidopa intestinal gel (LCIG) infusion and apomorphine subcutaneous infusion, are well‐established therapeutic options that have been shown in individual clinical studies to have approximately similar efficacy and to be relatively well tolerated [11, 12], although with different adverse event profiles [11], cost [13], and exclusion criteria [12]. LCIG, first developed in Uppsala, Sweden, by Professor Sten‐Magnus Aquilonius et al. during the 1990s, has a well‐demonstrated efficacy and tolerability for people with advanced PD [14, 15]. The addition of catechol‐O‐methyltransferase inhibitors (COMT‐I) to LCIG allows a significant reduction of total levodopa dose [16, 17, 18, 19]. A new formula was introduced in Sweden in 2019, the levodopa 20 mg/mL + entacapone 20 mg/mL + carbidopa 5 mg/mL intestinal gel (LECIG, Lecigon®/Lecigimon®, Britannia, UK) [12]. LECIG therapy comes in a 47 mL prefilled cartridge for continuous infusion into the upper small intestine through PEG‐J or T‐port [20] utilizing a discreet, wearable pump that weighs 134 g, the Crono LECIG pump (Canè, Italy) [12]. The pump has proven user‐friendliness and appreciated weight and size in patients previously treated with LCIG [21]. LECIG can theoretically reduce the consumption of B vitamins needed for the metabolism of administered levodopa both by reducing the total levodopa dose by at least 20% [12], and by the inhibition of COMT with entacapone as B vitamins are crucial for the function of COMT. This reduction of consumption of B vitamins theoretically, still to be proven, may reduce the risk for hyperhomocysteinemia. LECIG is presently available in several European countries, but data on efficacy, safety, and quality of life is limited in the literature [22, 23]. This study aims to summarize real‐world data from the Swedish national PD registry (ParkReg).
MATERIALS AND METHODS
Data collection was performed from ParkReg, part of the Swedish Neuro Registries (https://www.neuroreg.se). All patients in the ParkReg reported to receive LECIG during the period from 2019, when LECIG was reimbursed in Sweden, until 31 August 2022, were included. The latest data from up to 1 year before, and within 1 year after initiation of LECIG from the registry, were collected and pseudonymized. Collected data included several rating instruments; health‐related quality of life (HRQoL) scales in the form of the PD questionnaire‐8 (PDQ‐8), EuroQol (EQ‐5D‐5L) [24], nonmotor symptoms questionnaire (NMSQ) [25], and Movement Disorder Society‐Unified Parkinson's Disease Rating Scale part 4 (MDS‐UPDRS IV) for motor complications (time spent with dyskinesia 4:1; time spent in the OFF state 4:3). Objective data on plasma levels of homocysteine (P‐Hcy) and body mass index (BMI) were collected. Furthermore, data from the Parkinson KinetiGraph (PKG) [26, 27, 28] were collected. Patients were equipped with a wrist‐worn PKG watch, a movement recording system, continuously for 6 consecutive days. Data on motor patterns (bradykinesia, dyskinesia, fluctuations, and tremors) and immobility/somnolence were collected. The main outcomes from the PKG are bradykinesia score (PKG‐BKS), dyskinesia score (PKG‐DKS), fluctuations‐dyskinesia score (PKG‐FDS), percent time tremor (PKG‐PTT), and percent time immobility (PKG‐PTI).
Moreover, complications related to LECIG therapy, discontinuations, and deaths were collected as well, for the whole study period.
Dependent or independent t‐test was utilized when the assumed normal distribution of data was not rejected by the Shapiro‐Wilk test (two‐sided level of confidence α = 0.05), whereas the Wilcoxon signed‐rank test and Mann–Whitney test for paired and unpaired data, respectively, were used when data departed from normal distribution according to Shapiro‐Wilk test (two‐sided level of confidence α = 0.05).
The study was approved by the Swedish Ethical Review Authority, Sweden (Dnr 2020‐01610). A formal approval of nationwide data output from the steering committee of the Swedish Neuro Register was received.
RESULTS
A total of 150 patients receiving LECIG treatment were identified in ParkReg, of whom 61 were females (41%) and 89 were males (59%). The median age at LECIG initiation was 73 years (range 43–86; n = 150) and the median duration of motor symptoms was 17 years (IQR 9; n = 135). Out of the 150 patients, the Hoehn and Yahr (H&Y) scale was accessible for 42 of them, 25 patients (60%) of whom were at stage 2, followed by 13 patients (31%) at stage 3, and four patients (9%) at stage 4. Fifty out of the 150 patients (33%) switched from another DAT, most commonly LCIG (n = 39), followed by apomorphine subcutaneous infusion (n = 8), and DBS (n = 3). Meanwhile, two out of the 150 patients (1.3%) had concomitant DBS therapy.
At the initiation of LECIG, the mean values for morning bolus, continuous infusion, and on‐demand doses were 7.2 mL, 2.4 mL/h, and 1.2 mL, respectively. Table 1 presents available data from up to 1 year before and within 1 year after the initiation of LECIG. In Table 2, data are presented only for the subgroup of patients where the same data for the same individual patients was available both before and during LECIG. Median PDQ8‐SI score in the same subgroup of patients before and after initiation of LECIG decreased from 40.63% (IQR 25) to 31.25% (IQR 25), respectively (n = 33), as illustrated in Figure 1 (p = 0.018, median of differences 6.25%). Statistical analysis of individual items included in PDQ‐8 for the same patients showed a significant improvement only for question 7 (“Over the past four weeks have you, because of PD, had painful muscle cramps and pains?” p = 0.018). The objective motor fluctuation measures PKG‐FDS for the same individuals before and after LECIG was improved from a median of 11.55 (IQR 7.48) to 10 (IQR 5.02), respectively (n = 25), as illustrated in Figure 2 (p = 0.043, median of differences 0.7).
TABLE 1.
The latest data within 1 year before, and the latest data within 1 year after, initiation of LECIG for all patients during the study period (n = 150).
| Parameter | Before LECIG | Number of patients | On LECIG | Number of patients | Median (IQR) time of assessment (in days) after initiation of LECIG |
|---|---|---|---|---|---|
| MDS‐UPDRS part IV, time spent in the off state (4.3) Median (IQR): total hours OFF (h) | 4 (2.5) | 23 | 2 (2) | 17 | 165 (119) |
| MDS‐UPDRS part IV, dyskinesia (4.1) median (IQR): Total hours with dyskinesias (h) | 3 (3) | 19 | 2 (3.25) | 16 | 163 (176) |
|
PKG‐BKS, median (IQR) |
20.6 (7.6) |
41 |
23.3 (7.5) |
53 |
145 (144) |
|
PKG‐DKS, median (IQR) |
7.3 (9.5) |
41 |
8.3 (10) |
53 |
145 (144) |
|
PKG‐FDS, median (IQR) |
11.9 (7.6) |
41 |
10.3 (6.8) |
53 |
145 (144) |
|
PKG‐PTI, median (IQR) |
4.3 (6.7) |
41 |
3.5 (6.7) |
53 |
145 (144) |
| PKG‐PTT, median (IQR) | 1 (2.6) | 41 |
0.7 (1.4) |
53 |
145 (144) |
| PDQ‐8‐SI (%), median (IQR) | 25 (10.2) | 59 | 31.25 (26) | 52 | 214 (145) |
| EQ‐5D, median (IQR) | 0.62 (0.26) | 46 | 0.62 (0.32) | 41 | 192 (56) |
| NMSQ, median (IQR) | 14 (7.5) | 38 | 13 (6) | 45 | 176 (78) |
| P‐Hcy (μmol/L), median (IQR) | 13 (4) | 37 | 12 (4.7) | 44 | 169 (240) |
| BMI (kg/m2), mean (SD) | 24.4 (3.9) | 38 | 24.3 (4.2) | 38 | 136 (61) |
TABLE 2.
The latest data for the subgroups of patients with available data both within 1 year before and within 1 year after, initiation of LECIG during the study period.
| Parameter | Before LECIG | On LECIG | n | Data collection in days after LECIG start, (median [range]) | Statistical analysis and results |
|---|---|---|---|---|---|
| MDS‐UPDRS part IV, dyskinesia (4.1) means (SD): total hours with dyskinesias (h) |
3 (1.4) |
2.3 (1.8) |
7 |
188 (55–296) |
p = 0.46, 95% CI −2.9–1.5 |
| MDS‐UPDRS part IV, time spent in the off state (4.3) means (SD): total hours OFF (h) |
4 (1.7) |
3 (2.5) |
6 |
207.5 (169–296) |
p = 0.31, 95% CI −3.2–1.2 |
| PKG‐BKS, median (IQR) |
21.1 (7.5) |
23.4 (6.6) |
26 |
134 (21–276) |
p = 0.27 |
| PKG‐DKS, median (IQR) |
8.8 (9.5) |
6.3 (8) |
26 |
134 (21–276) |
p = 0.09 |
| PKG‐FDS, median (IQR) |
11.6 (7.48) |
10 (5) |
26 |
134 (21–276) |
p = 0.04* |
| PKG‐PTI (%), median (IQR) |
3.3 (6.7) |
2.1 (6.4) |
26 |
134 (21–276) |
p = 0.17 |
| PKG‐PTT (%), median (IQR) |
1.2 (2.57) |
0.8 (1.9) |
26 |
134 (21–276) |
p = 0.8 |
| PDQ‐8 SI (%), median (IQR) |
40.63 (25) |
31.3 (25) |
33 |
186 (17–316) |
p = 0.01* |
| EQ‐5D‐5L SI, median (IQR) |
0.6 (0.2) |
0.6 (0.3) |
25 |
175 (52–349) |
p = 0.07 |
| NMSQ, median (IQR) |
13 (8.5) |
12 (6) |
21 |
169 (52–296) |
p = 0.08 |
| P‐Hcy (μmol/L) Median (IQR) |
12.8 (5.1) |
13 (3.4) |
20 |
147.5 (4–364) |
p = 0.15 |
| BMI (kg/m2), mean (SD) |
24.4 (4.2) |
24.2 (4.5) |
33 |
139 (74) |
p = 0.28, 95% CI –0.78–0.23 |
p < 0.05.
FIGURE 1.
Median PDQ8‐SI score in the same individual patients decreased during LECIG treatment from 40.63% to 31.25% (p = 0.018; n = 33). *p < 0.05.
FIGURE 2.
Median PKG‐FDS decreased during LECIG therapy from 11.5 to 10 (p = 0.043, n = 25). *p < 0.05.
The frequency of different LECIG‐related complications, as reported to the Swedish ParkReg, is shown in Table 3. Twenty of 150 (13.3%) patients discontinued LECIG, and 11 (7.3%) patients died while on LECIG.
TABLE 3.
Reported adverse effects while still on LECIG, according to the Swedish PD Register.
| Reported adverse events | Patients, n (% of total N = 150) |
|---|---|
| Tube‐related | 29 (19%) |
| PEG‐J stoma‐related | 16 (11%) |
| Neuropsychiatric | 7 (5%) |
| Diarrhea | 1 (1%) |
| Weight loss | 2 (1%) |
| Anaemia | 1 (1%) |
| Intermittent double vision | 1 (1%) |
| Sepsis | 1 (1%) |
| Death while on LECIG | 11 (7%) |
Note: Please note that the frequencies of adverse events may be underreported because they are not mandatory.
P‐Hcy levels were generally within the normal range while receiving LECIG (Tables 1 and 2). No significant differences in P‐Hcy levels before and while receiving LECIG could be demonstrated.
DISCUSSION
This nationwide, registry‐based, real‐world data analysis is the first multicenter study on LECIG treatment in Sweden. Patients started on LECIG had longstanding PD (median onset of motor symptoms was 17 years) and 50 of 150 (33%) patients were switched from another DAT.
Available data for patients during LECIG showed good symptom control. The degree of fluctuations and dyskinesia shown as PKG‐FDS, and the HRQoL shown as PDQ8‐SI were improved when analyzed in the group of patients where the same data were available both before and while on LECIG for the same individual patients. The translation of PDQ8‐SI and EQ‐5D index values to a sensible realistic grade of health and defining minimal clinically important difference (MCID) in EQ‐5D‐5L index value for PD and PDQ8‐SI is complex [29, 30], unascertained for Swedish patients. Regarding the group of patients, where the latest data were available both before and during LECIG, an improvement was shown in health‐related quality of life by PDQ8‐SI with a difference in medians of 9.4 units, which is above the proposed MCID [29]. Meanwhile, it is worth noting that a similar statistically significant improvement in HrQoL, measured by EQ‐5D, could not be shown. Nevertheless, the EQ‐5D score did not deteriorate as it would be expected for this group of patients. In parallel, target values for PKG parameters have been suggested [26, 27, 28], and even though we could show a statistically significant improvement in PKG‐FDS, the clinical relevance of the improvement is unclear because the value was within the proposed target interval both before and during LECIG.
No statistically significant decrease in NMSQ score could be shown for the group of patients, where the latest data, within 1 year, were available both before and during LECIG (n = 21). The NMSQ score is, however, a screening instrument for the presence of nonmotor symptoms in PD patients and does not address the severity of symptoms.
Complications reported to ParkReg were mainly tube‐ and stoma‐related. The complication reporting rate in the registry is likely to be lower than can be expected with other study designs such as a controlled clinical trial. Eleven of 150 (7.33%) patients were deceased, which is within the expected mortality in a population with long PD duration [31, 32]. Data about the cause of death was unavailable and it is therefore unknown if any of the deaths was related to LECIG treatment. Further investigation may be warranted.
Plasma Hcy levels during LECIG were generally low, and no significant change in P‐Hcy could be demonstrated after LECIG initiation. No information was available about concomitant B vitamin supplementation, kidney function, or oral entacapone treatment before initiating LECIG. According to Scandinavian guidelines, B12 and B9 supplementation should be used with levodopa infusions, with further addition of B6 if/when increased P‐Hcy despite B12 and B9 supplementation [33]. Thus, most Swedish patients on LCIG and LECIG are likely under at least B9 and B12 vitamin supplement treatment. High doses of levodopa for a long time are associated with an increased risk for hyperhomocysteinemia and possibly diseases associated with it, such as cardiovascular accidents [34], cognitive impairment [35], and polyneuropathy [36], although the causality is not clear. One of the interesting questions in this context is whether the addition of COMT‐I to LCIG and thus a lower dose of levodopa, reduces the risk for hyperhomocysteinemia [37] and associated diseases. The hypothetical COMT‐I‐related risk reduction for hyperhomocysteinemia and associated complications remains to be determined.
The present study has some important limitations. First, the ParkReg presently has only 63% coverage of all patients treated with DATs. Improvement measures are applied through an ongoing campaign aiming to achieve complete coverage of DAT‐treated patients in ParkReg. Most patients who receive LECIG are offered contact with support nurses, and their records show that 241 patients received LECIG during 2019–2022 in Sweden (personal communication). Accordingly, our study sample covered 62% of all patients. Incomplete registration in ParkReg is thus a major limitation to be considered, including the limited density of data for patients within the registry, for example, regarding the MDS‐UPDRS part IV items about dyskinesias and “off” time and concomitant medication. Nevertheless, the study reflects the real‐world use of LECIG in Sweden in a way that a carefully planned clinical trial would not do. For example, patients with dementia or complex treatment regimens would probably be excluded to a higher extent in a clinical trial compared with clinical practice. Earlier initiation of LECIG is to be considered.
To conclude, even though the long‐term efficacy and tolerability of LECIG need to be further investigated, we present here data on LECIG therapy based on up to 3‐year follow‐up of 150 patients in routine care in Sweden, showing that LECIG is an effective and safe alternative for the management of advanced PD.
FUNDING INFORMATION
The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement. No funding from the industry.
CONFLICT OF INTEREST STATEMENT
MÖ has no conflicts of interest to declare relevant to this work. FB has received lecture fees from AbbVie and owns stock options in Dizlin AB. PO has received lecture fees and advisory board fees from AbbVie, Bial, Britannia, Nordic Infucare, Stada, and Zambon. MS has served as a consultant to AbbVie, TLV, and Convatec. AJ's institution received remuneration from AbbVie for lectures. IM has received lecture fees from AbbVie. PS has received lecture fees and advisory board fees from AbbVie, Lundbeck, and Zambon. ND has received lecture fees and advisory board fees from AbbVie, Zambon, and NordicInfu Care and is the founder of Dizlin AB. DN has served as a Britannia Pharmaceuticals Ltd. consultant and received lecture fees and advisory board fees from AbbVie, NordicInfu Care, and Stada Arzneimittel AG.
ACKNOWLEDGMENTS
Jonathan Timpka (Lund), Karin Gunnarsson (Örebro), and Linda K. Eriksson (Umeå) have, among others, contributed data to ParkReg.
Öthman M, Bergquist F, Odin P, et al. Levodopa–entacapone–carbidopa intestinal gel: Data from the Swedish national registry for Parkinson's disease. Eur J Neurol. 2025;32:e16582. doi: 10.1111/ene.16582
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.