This systematic review of the literature, which includes 27 studies, is the most comprehensive qualitative synthesis of data on the long-term (≥ 12 months follow-up from treatment initiation) impact of levodopa/carbidopa intestinal gel on ‘off’-time in patients with advanced Parkinson’s disease |
Of the 27 studies, 14 (52%) were multicentre studies and 10 (37%) had a sample size of ≥ 50 patients. Study follow-ups ranged from 12–120 months with 15 (56%) studies having follow-ups ≥ 24 months |
Treatment of advanced Parkinson’s disease with levodopa/carbidopa intestinal gel was observed to be consistently effective in significantly reducing ‘off’-time within 3 months, and this improvement is maintained in the long-term, even after 24 months |
The improvement in ‘off’-time may be associated with clinically meaningful improvement in health-related quality of life in the long term |
Safety issues with levodopa/carbidopa intestinal gel are most frequently related to the procedure or the device, and the emergence of unexpected adverse events in the long-term is not frequent |
Dose optimisation of levodopa/carbidopa intestinal gel allows personalisation of treatment that should further enhance the maintenance of long-term efficacy |
Digital Features
Introduction
Methods
Data Sources
Search Strategy
Eligibility Criteria
Screening, Selection and Data Extraction
Results
Search Results and Study Selection
Long-Term ‘Off’-time
Study | Na | Age (years)b | Disease duration (years)b | Mean follow-up (months) | Baseline ‘off’-timec | Reduction from baseline in ‘off’-time at end of follow-up (%) | Reduction from baseline in ‘off’-time at specific timepoints (%) | |||
---|---|---|---|---|---|---|---|---|---|---|
3–6 months | 1 year | 2 years | 3–5 years | |||||||
‘Off’-time assessed by UPDRS IV item 39 (score) | ||||||||||
Lopiano et al. 2019 [51] | 145 | 70.4 (7.7) | 14.6 (6.5) | 36d | 2.0 | 50* | nr | 55* | nr | nr |
Fabbri et al. 2019 [49] | 44 | 67.4 (5.8) | 14.0 (5.8) | 52d | 2.0 | 60* | nr | nr | nr | nr |
Zibetti et al. 2018 [27] | 32 | 67.5 (6.9) | 14.0 (4.2) | 31d | 2.1 | 62* | nr | nr | nr | nr |
Antonini et al. 2017 [19] | 375 | 66.4 (8.8) | 12.7 (6.3) | 24 | 6.0i | 65* | 70* | 68* | 68* | nr |
Merola et al. 2016 [28]e | 20 | 64.6 (7.0) | 13.8 (2.6) | 62d | 1.7 | 55* | nr | nr | nr | nr |
Calandrella et al. 2015 [29] | 35 | 64.8 (13.5) | 12.3 (3.9) | 32d | 2.4 | 54* | nr | nr | nr | nr |
Caceres-Redondo et al. 2014 [30] | 29 | 66.5 (9.3) | 15.1 (5.4) | 24 | 2.9f | 58* | nr | nr | nr | nr |
Zibetti et al. 2014 [31] | 59 | 69.3 (5.9) | 13.0 (3.8) | 26d | 1.8 | 49* | nr | nr | nr | nr |
Sensi et al. 2014 [32] | 28 | 67.6 (6.1) | 15.5 (4.0) | 24 | 2.3 | 57* | 48* | nr | 57* | nr |
Antonini et al. 2013 [33] | 98 | 65.3 (10.4) | 14.9 (6.6) | 24 | 1.6 | 38* | 47* | 33* | 37 | nr |
Zibetti et al. 2013 [34] | 25 | 69.9 (5.8) | 12.1 (4.1) | 36d | 1.6 | 50* | nr | nr | nr | nr |
Fasano et al. 2012 [47] | 14 | 67.1 (11.5) | 12.9 (4.8) | 25d | nr | 49* | nr | nr | nr | nr |
Merola et al. 2011 [35]e | 20 | 69 (5.9) | 13.9 (4.5) | 15d | 1.6 | 68* | nr | nr | nr | nr |
Antonini et al. 2010 [36] | 19 | nr | nr | 14d | 1.6 | 68* | 52 | 36 | 52 | 68* |
Antonini et al. 2008 [37] | 22 | nr | nr | 24 | 2.6 | 46* | nr | 54* | 46* | nr |
‘Off’-time assessed by patient diary (h/day) | ||||||||||
Fernandez et al. 2018 [48]g | 86 | 65.1 (8.3) | 10.5 (4.5) | 49d | 6.0 h | 67* | nr | nr | nr | nr |
Standaert et al. 2017 [50] | 38 | 64.3 (10.2) | 11.5 (5.3) | 14 | 6.6 | 74* | 61* | nr | nr | nr |
De Fabregues et al. 2017 [38] | 37 | 68.2 (6.8) | 13.5 (5.6) | 120 | 6.0 | 83* | 82* | nr | 82* | 83* |
Juhasz et al. 2017 [39]j | 34 | 67 (6) | 12 (5) | 12 | 6.3 | 84* | nr | 84* | nr | nr |
Chang et al. 2016 [40] | 15 | 62 (4.7) | 14 | 12 | 6.3 | 71 | 70 | 71 | nr | nr |
Slevin et al. 2015 [41]k | 62 | 64.8 (6.6) | 11.4 (5.7) | 13 | 5.1 | 46* | nr | 46* | nr | nr |
Fernandez et al. 2015 [20] | 354 | 64.1 (9.1) | 12.5 (5.5) | 14 | 6.8 | 66* | 64* | 66* | nr | nr |
Foltynie et al. 2013 [42] | 12 | 66f | 23.2f | 12 | 4.7 l | 43 | nr | 43 | nr | nr |
Eggert et al. 2008 [43] | 13 | 65 (44–71)m | 17 (10–26)m | 12 | 8.0f | 70 | 78* | 70 | nr | nr |
‘Off’-time assessed by healthcare provider (h/day) | ||||||||||
Valldeoriola et al. 2016 [44] | 177 | 70.6 (8.4) | 14.3 (6.9) | 35 | 7.6 l | 66* | nr | nr | nr | nr |
Buongiorno et al. 2015 [45] | 72 | 68.4 (7.3) | 13.1 (5.1) | 22d | 6.8 | 56* | nr | nr | nr | nr |
Lundqvist et al. 2014 [46] | 10 | 64 (58–70)m | 10 (2) | 12 | 1.1 l | 71* | nr | 71* | nr | nr |
Other Motor Symptoms
Study | UPDRS II total scorea, b | UPDRS III total scorea, b | ||
---|---|---|---|---|
Baseline | Follow-upc | Baseline | Follow-upc | |
Lopiano et al. 2019 [51] | ‘Off’: 29.2 (9.6) ‘On’: 18.2 (9.4) | ‘Off’’: 25.5 (8.8)* ‘On’: 16.2 (8.5)* | nr | nr |
Fabbri et al. 2019 [49] | 17.1 (7.2) | 29.5 (9.6)* | 31.0 (12.4) | 49.2 (15.0)* |
Zibetti et al. 2018 [27] | ‘On’: 13.3 (6.0) | ‘On’: 12.9 (6.9) | ‘On’: 23.5 (9.9) | ‘On’: 22.8 (13.4) |
Fernandez et al. 2018 [48] | 3.1 (7.8)d,e* | 4.6 (14.7)d,e* | ||
Standaert et al. 2017 [50] | ‘On’: 16.7 (6.5) | − 4.8 (0.7)e* (1 wk) − 5.5 (0.9)e* (12 wk) − 4.2 (0.9)e* (36 wk) − 4.7 (0.9)e* (60 wk) | ‘On’: 25.0 (13.2) | − 3.5 (1.2)e* (1 wk) − 5.6 (1.2)e* (12 wk) − 2.6 (1.5)e (36 wk) − 3.6 (1.5)e* (60 wk) |
Antonini et al. 2017 [19] | ‘On’: 16.5 (9.8) | − 2.0 (9.1)e* (18 mo) | ‘On’: 24.6 (12.0) | − 1.9 (11.8)e* |
De Fabregues et al. 2017 [38] | nr | nr | ‘Off’: 40.9 (13.2) ‘On’: 22.2 (8.4) | ‘Off’: 39.0 (12.0)* (3 mo) ‘On’: 21.1 (8.8) (3 mo) |
Juhasz et al. 2017 [39] | 23.9 (6.2) | 19.4 (9.0)* | 42.5 (16.0) | 45.3 (16.4) |
Merola et al. 2016 [28]f | 7.8 (3.5) | 13.5 (9.8) | ‘Off’: 41.3 (9.0) ‘On’: 19.9 (11.4) | ‘Off’: 53.8 (13.0) ‘On’: 23.9 (10.1) |
Chang et al. 2016 [40] | nr | nr | ‘On’: 31 (36)%e (6 mo) ‘On’: 37 (11)%e (12 mo) | |
Valldeoriola et al. 2016 [44] | ‘Off’’: -2.3 (23.2)e ‘On’: 3.1 (19.0)e | nr | nr | |
Calandrella et al. 2015 [29] | nr | nr | ‘On’: 36.5 (2.4) | ‘On’: 28.5 (5.0)* |
Slevin et al. 2015 [41]g | ‘On’: − 1.0 (7.0)e | − 0.5 (10.4)e | ||
Fernandez et al. 2015 [20] | ‘On’: − 4.4 (6.5)e* | 28.8 (13.7) | Sig. improvement (12 mo) | |
Buongiorno et al. 2015 [45] | ‘On’: 13.6 | ‘On’: 14.3 | ‘On’: 21.9 | ‘On’: 22.3 |
Caceres-Redondo et al. 2014 [30] | ‘Off’: 27.2 (8.5) ‘On’: 14.5 (5.3) | ‘Off’: 23.8 (5.9)* ‘On’: 16.5 (5.0) | ‘Off’: 48.0 (8.9) ‘On’: 27.2 (8.1) | ‘Off’:45.5 (8.9) ‘On’: 29.5 (6.4) |
Zibetti et al. 2014 [31] | nr | nr | nr | nr |
Sensi et al. 2014 [32] | nr | nr | ‘On’: 35.5 (11.5) | ‘On’: 33.4 (10.8) (6 mo) ‘On’: 34.7 (12.4) (24 mo) |
Lundqvist et al. 2014 [46] | nr | nr | nr | nr |
Antonini et al. 2013 [33] | ‘On’: 14.8 (8.9) | ‘On’: 10.6 (7.2)* (6 mo) ‘On’: 11.8 (8.2)* (12 mo) ‘On’: 14.0 (7.5) (24 mo) ‘On’: 13.2 (8.5) (last f-u) | ‘On’: 25.3 (13.6) | ‘On’: 22.6 (12.9)* (6 mo) ‘On’: 23.3 (12.5) (12 mo) ‘On’: 27.1 (13.4) (24 mo) ‘On’: 24.5 (13.0) (last f-u) |
Zibetti et al. 2013 [34] | ‘Off’: 23.2 (8.5) ‘On’: 16.1 (7.2) | ‘Off’: 25.3 (7.3) ‘On’: 20.9 (7.5)* | ‘Off’: 43.1 (13.7) ‘On’: 23.2 (9.2) | ‘Off’: 48.4 (12.4)* ‘On’: 32.2 (12.6)* |
Foltynie et al. 2013 [42] | nr | nr | nr | nr |
Fasano et al. 2012 [47] | No significant change | No significant change | ||
Merola et al. 2011 [35]f | ‘Off’: 25.9 (8.6) | ‘Off’: 18.3 (7.6)* | ‘Off’: 45.7 (14.8) | ‘Off’: 29.1 (15.9)* |
Antonini et al. 2010 [36] | nr | nr | nr | nr |
Antonini et al. 2008 [37]h | 12.8 (2.9) | 9.4 (3.9)* | ‘On’: 24.6 (5.2) | ‘On’: 24.8 (6.0) |
Eggert et al. 2008 [43] | nr | nr | nr | nr |
Study | UPDRS IV total scorea | Dyskinesiaa | Other changesa | |||
---|---|---|---|---|---|---|
Baseline | Follow-upb | Baseline | Follow-upb | Baseline | Follow-upb | |
Lopiano et al. 2019 [51] | 8.2 (3.3) | 4.9 (3.1)* | 1.8 (1.0) UPDRS IV item 32 1.5 (1.1) UPDRS IV item 33 0.8 (1.0) UPDRS IV item 34 | 1.3 (1.0)* UPDRS IV item 32 0.9 (1.0)* UPDRS IV item 33 0.4 (0.7)* UPDRS IV item 34 | ‘Off’: 4.0 (0.8) UPDRS-V ‘On’: 3.1 (0.8) UPDRS-V | ‘Off’: 3.7 (0.8)* UPDRS-V ‘On’: 2.8 (0.8)* UPDRS-V |
Fabbri et al. 2019 [49] | 9.5 (3.1) | 6.1 (2.4)* | 1.7 (1.0) UPDRS IV item 32 | 1.7 (0.8) UPDRS IV item 32 | 3.0 (0.9) H&Y 63 (13) S&E | 3.3 (1.2)* H&Y 56 (19)* S&E |
Zibetti et al. 2018 [27] | 9.2 (2.5) | 6.1 (2.5)* | 1.8 (1.0) | 1.4 (0.9)* | 2.4 (0.9) H&Y 77.8 (15.2) S&E | 2.8 (0.9)* H&Y 66.3 (19.1)* S&E |
Fernandez et al. 2018 [48] | nr | nr | Unchangedc,d | nr | nr | |
Standaert et al. 2017 [50] | 8.7 (3.0) | − 2.7 (0.5)d* (1 wk) − 3.5 (0.4)d* (12 wk) − 3.5 (0.4)d* (36 wk) − 2.9 (0.6)d* (60 wk) | 3.0 (2.1) UPDRS IV item 32, 33, 34 | − 1.1 (0.4)d* (1 wk) − 1.1 (0.3)d* (12 wk) − 1.1 (0.3)d* (36 wk) − 0.6 (0.6)d (60 wk) UPDRS IV item 32, 33, 34 | nr | nr |
Antonini et al. 2017 [19] | nr | nr | 4.3 (3.8) Modified UPDRS IV item 32 | − 1.1 (4.7)d* Modified UPDRS IV item 32 | nr | nr |
De Fabregues et al. 2017 [38] | nr | nr | Reduced in 16.1% | 50 S&E | 80* (3 mo) S&E ‘Off’ Improved in 45.9%* H&Y ‘On’ Improved in 27%* H&Y | |
Juhasz et al. 2017 [39] | 10.4 (4.0) | 7.5 (4.0)* | 2.8 (1.1) MDS-UPDRS item 4.1 4.9 (2.8) PD diary (‘on’-time without dyskinesia) 3.6 (2.5) PD diary (‘on’-time with slight dyskinesia) 1.8 (1.7) PD diary (‘on’-time with severe dyskinesia) | 2.1 (1.2)* MDS-UPDRS item 4.1 10.0 (4.6)* PD diary (‘on’-time without dyskinesia) 4.0 (4.4) PD diary (‘on’-time with slight dyskinesia) 0.4 (1.6 PD diary (‘on’-time with severe dyskinesia) | 45.9 (16.7) UPDyRS 60.0 (17.3) S&E | 32.1 (17.3)* UPDyRS 67.4 (17.3) S&E |
Merola et al. 2016 [28]e | 8.3 (2.6) | 6.2 (2.1) | − 9.0%d Duration − 18.0%d Severity | 2.4 (0.7) H&Y 84.5 (12.1) S&E | 3.0 (0.9) H&Y 78.8 (17.5) S&E | |
Chang et al. 2016 [40] | nr | nr | nr | nr | nr | nr |
Valldeoriola et al. 2016 [44] | nr | nr | 21.6 (16.5) ‘On’-time without disabling dyskinesia 11.3 (13.0) ‘On’-time with disabling dyskinesia | 55.6 (25.7)* ‘On’-time without disabling dyskinesia 10.9 (16.6) ‘On’-time with disabling dyskinesia | 88.6% improvement CGI-C 86.8% improvement PGI-C | |
Calandrella et al. 2015 [29] | nr | nr | 2.2 (0.7) UPDRS IV item 32 + 33 | 1.5 (0.7)* UPDRS IV item 32 + 33 | No change H&Y | |
Slevin et al. 2015 [41]f | − 1.4 (3.0)d* | 2.2 (3.7)d* ‘On’-time with troubling dyskinesia | 2.3 (1.6)d* CGI-I | |||
Fernandez et al. 2015 [20] | nr | nr | 4.8 (3.4)d* ‘On’-time without dyskinesia − 0.4 (2.8)d* ‘On’-time with dyskinesia | nr | nr | |
Buongiorno et al. 2015 [45] | nr | nr | 1.4 (1.3) UPDRS IV item 33 30% %age of day with dyskinesia | 1.2 (1.2) UPDRS IV item 33 40%* %age of day with dyskinesia | nr | 70% subjective improvement CGI |
Caceres-Redondo et al. 2014 [30] | 8.7 (2.3) | 6.7 (2.8)* | 60.3 (37.8) UPDRS IV item 32 | 48.8 (28.7)* UPDRS IV item 32 | ‘Off’: 3.7 (0.8) H&Y ‘On’: 2.4 (0.5) H&Y | ‘Off’: 3.5 (1.1) H&Y ‘On’: 2.7 (0.7) H&Y |
Zibetti et al. 2014 [31] | 8.5 (3.1) | 5.7 (2.4)* | 1.7 (0.9) UPDRS IV item 32 | 1.2 (0.7)* UPDRS IV item 32 | nr | nr |
Sensi et al. 2014 [32] | 8.4 (2.5) | 5.6 (2.7)* (6 mo) 4.4 (1.9)* (24 mo) | 2.2 (1.0) UPDRS IV item 32 | 1.8 (1.0) (6 mo) 1.2 (1.0)* (24 mo) UPDRS IV item 32 | 3.2 (0.7) H&Y | 3.1 (0.8) (6 mo) H&Y 3.0 (0.8) (24 mo) H&Y |
Lundqvist et al. 2014 [46] | nr | nr | 10.0 (9.2)% | 2.0 (2.8)%* | 2–3 H&Y range 75% S&E 48.9 (10.0) Total UPDRS | 1.5–3 H&Y range 79% S&E 30.2 (5.2)* Total UPDRS |
Antonini et al. 2013 [33] | nr | nr | 1.7 (1.0) UPDRS IV item 32 | 1.2 (0.9)* (6 mo) 1.5 (0.8) (12 mo) 1.4 (0.8) (24 mo) 1.3 (0.9)* (last f-u) | nr | nr |
Zibetti et al. 2013 [34] | 8.4 (3.2) | 5.6 (2.8)* | 1.9 (1.0) UPDRS IV item 32 | 1.1 (1.0)* UPDRS IV item 32 | nr | nr |
Foltynie et al. 2013 [42] | nr | nr | 16.6 (18.6)% | 8.2 (10.3)% | nr | nr |
Fasano et al. 2012 [47] | 29.3%d* | 38.5% d* UPDRS IV item 32 | 2.7 (1.8) ADL score 2.9 (2.5) IADL score | 3.6 (3.5) ADL score 4.0 (2.6) IADL score | ||
Merola et al. 2011 [35]e | 8.6 (4.2) | 5.6 (3.4)* | No change UPDRS IV item 32 | nr | nr | |
Antonini et al. 2010 [36] | nr | nr | 2.5 (0.6) UPDRS IV item 32 | 1.3 (0.9) (1–20 wk) 1.4 (0.6) (21–50 wk) 1.5 (0.6) (51–100 wk) 1.0 (0.0)* (101–200 wk) UPDRS IV item 32 | nr | nr |
Antonini et al. 2008 [37]g | 8.4 (0.8) | 6.6 (0.9)* | No change UPDRS IV item 32 | nr | nr | |
Eggert et al. 2008 [43] | nr | nr | 17 (15)% | 5 (6)%* | nr | nr |
Non-Motor Symptoms and Quality of Life
Study | NMSS total or sub-domain scoresa | MMSE total scorea | UPDRS I total score and other NMS measuresa | |||
---|---|---|---|---|---|---|
Baseline | Follow-up | Baseline | Follow-up | Baseline | Follow-up | |
Lopiano et al. 2019 [51] | nr | nr | nr | nr | ‘Off’ 6.8 (4.8) ‘On’ 4.3 (3.1) UPDRS I 25 (10.4) PDSS-2 10.4 (16.6) QUIP 40.2 (12.4) RSS-2 | ‘Off’ 6.0 (3.7)* ‘On’ 3.8 (2.8)* UPDRS I 22.7 (10.1)* PDSS-2 7.1 (10.1)* QUIP 38.3 (13) RSS-2 |
Fabbri et al. 2019 [49] | nr | nr | 27.2 (2.4) | 24.1 (4.0)* | 14.5 (7.8) BDI | 18.5 (9.5)* BDI |
Standaert et al. 2017 [50] | 48.3 (35.6) Total score | − 17.6 (3.6)b* (12 wk) Total score − 11.8 (4.0)b* (60 wk) Total score 5/9 sub-domains (attention/memory, sleep/fatigue, gastrointestinal, sexual function and miscellaneous) significantly improved | nr | nr | 1.6 (1.6) UPDRS I | − 0.6 (0.2)* (1 wk) UPDRS I − 0.3 (0.3) (12 wk) UPDRS I − 0.3 (0.3) (36 wk) UPDRS I − 0.1 (0.3) (60 wk) UPDRS I |
Antonini et al. 2017 [19] | 69.2 (42.1) Total score | − 14.4 (44.8)b* Total score 5/9 sub-domains (mood/cognition, sleep/fatigue, gastrointestinal, cardiovascular function and miscellaneous) significantly improved | nr | nr | nr | nr |
De Fabregues et al. 2017 [38] | nr | nr | Median 28 | Median 29 (3 mo) | 3.2 (2.4) UPDRS I | 2.5 (1.7)* (3 mo) UPDRS I |
Juhasz et al. 2017 [39] | 88.9 (40.3) Total score | 32.2 (69.0)* Total score 2/9 sub-domains (mood problems and cardiovascular function) significantly improved | nr | nr | 27.2 (10.5) PDSS 9.1 (4.8) ESS | 23.2 (12.0)* PDSS 4.6 (7.0) ESS |
− 19.0 (10.0) LARS | − 20.4 (7.4) LARS | |||||
18.2 (7.2) MADRS 19.7 (6.9) MDS-UPDRS nM-EDL | 15.4 (6.2)* MADRS 16.7 (6.9)* MDS-UPDRS nM-EDL | |||||
Valldeoriola et al. 2016 [44] | Proportion of patients with sub-domain improvements: Dizziness 59.7% Daytime fatigue 57.5% Mood 56.0% Falling asleep in the day 52.6% Insomnia 52.3% Sadness 50.9% | nr | nr | nr | nr | |
Merola et al. 2016 [28] | nr | nr | 29.3 (0.7) | 26.6 (4.3) | 2.1 (1.9) UPDRS I | 3.4 (3.7) UPDRS I |
Slevin et al. 2015 [41]c | nr | nr | nr | nr | 0.7 (1.7)b | |
Caceres-Redondo et al. 2014 [30] | 17.3 (4.7) Total score | 14.2 (4.3)* Total score 2/9 sub-domains (sleep/fatigue and gastrointestinal) significantly improved | 24.7 (3.5) | 22.0 (4.9)* | 124.9 (17.8) DRS | 115.3 (23.6)* DRS No change in NPI-Q |
Sensi et al. 2014 [32] | 51.8 (37.3) Total score | 44.6 (25.6) (6 mo) Total score 38.0 (24.7) (24 mo) Total score | 25.0 (2.7) | 24.4 (2.8) (6 mo) 23.2 (4.1)* (24 mo) | nr | nr |
Zibetti et al. 2013 [34] | nr | nr | 24.7 (2.7) | 15.6 (3.7)* | nr | nr |
Fasano et al. 2012 [47] | 126.0 (56.2) Total score | 108.3 (49.4) Total score | 22.2 (5.6) | 22.4 (6.0) | 8.7 (3.2) UPDRS I 39.1 (8.6) PDSS 0.6 (0.5) QUIP 41.2 (30.7) NPI 11.9 (3.8) FAB 33.9 (8.0) RSS | 6.8 (2.9)* UPDRS I 33.5 (9.2)* PDSS 0.3 (0.5)* QUIP 27.4 (23.0)* NPI 11.8 (3.9) FAB 29.5 (8.0) RSS |
Merola et al. 2011 [35] | nr | nr | nr | nr | 3.9 (2.3) UPDRS I | 4.3 (2.2) UPDRS I |
Study | PDQ-39 or PDQ-8 scoresa | Other QoL scalesa | ||
---|---|---|---|---|
Baseline | Follow-up | Baseline | Follow-up | |
Fernandez et al. 2018 [48] | 0.5 (16.6)b PDQ-39 | nr | nr | |
Standaert et al. 2017 [50] | 34.7 (13.0) PDQ-39 | − 4.8 (1.8)b* (1 wk) PDQ-39 − 11.2 (2.8)b* (12 wk) PDQ-39 − 9.1 (2.2)b* (30 wk) PDQ-39 − 10.2 (2.6)b* (60 wk) PDQ-39 | nr | nr |
Antonini et al. 2017 [19] | 46.8 (18.6) PDQ-8 | − 5.3 (20.7)b* PDQ-8 | 0.4 (0.3) EQ-5D | 0.06 (0.34)b* EQ-5D |
De Fabregues et al. 2017 [38]c | 56.9 (11.4) PDQ-39 | 41.9 (21.5) (1 wk) PDQ-39 35.7 (18.6) (3 mo) PDQ-39 35.5 (19.1)* (6 mo) PDQ-39 35.5 (18.8)* (1 yr) PDQ-39 | 9.3 (1.7) EQ-5D: BL 1 year 7.5 (1.9) (p = 0.042) | 7.9 (2.6)* (1 wk) EQ-5D 7.5 (2.1)* (3 mo) EQ-5D 8.2 (2.5) (6 mo) EQ-5D 7.5 (1.9)* (1 yr) EQ-5D |
Juhasz et al. 2017 [39] | 38.5 (14.9) PDQ-39 | 29.6 (13.6)* PDQ-39 | 0.5 (0.2) EQ-5D index | 0.6 (0.3)* EQ-5D index |
Chang et al. 2016 [40] | 38.3 (14.0) PDQ-39 | 22.8 (17.0) (6 mo) PDQ-39 24.5 (16.0) (1 yr) PDQ-39 | nr | nr |
Slevin et al. 2015 [41]d | − 3.5 (13.4)b PDQ-39 | − 0.006 (0.220)b EQ-5D summary index | ||
Fernandez et al. 2015 [20] | − 6.9 (14.1)b* PDQ-39 | − 0.064 (0.203)b* EQ-5D summary index | ||
Caceres-Redondo et al. 2014 [30] | 84.2 (18.7) PDQ-39 | 74.3 (21.3)* PDQ-39 | nr | nr |
Zibetti et al. 2014 [31] | nr | nr | Great improvement 44% Moderate improvement 48% Unspecified 5-point scale | |
Sensi et al. 2014 [32] | 46.3 (13.7) PDQ-8 | 29.9 (17.0)* PDQ-8 | 87.8 (19.5) SQLC | 94.4 (20.3) SQLC |
Lundqvist et al. 2014 [46] | nr | nr | 0.6 (0.1) 15D | 0.7 (0.1) (3 mo) 15D 0.7 (0.1) (6 mo) 15D 0.7 (0.1) (9 mo) 15D 0.7 (0.1) (12 mo) 15D 0.7 (0.1) (last f-u) 15D |
Antonini et al. 2013 [33] | 53.3 (21.7) PDQ-8 | 47.0 (15.2)* PDQ-8 | nr | nr |
Zibetti et al. 2013 [34] | 59.2 (18.7) PDQ-39 | 43.1 (13.9)* PDQ-39 | nr | nr |
Foltynie et al. 2013 [42] | 49.7 (10.4) PDQ-39 | 38.7 (11.2)* PDQ-39 | nr | nr |
Fasano et al. 2012 [47] | 18.1 (6.6) PDQ-8 | 16.7 (6.0) PDQ-8 | nr | nr |
Antonini et al. 2008 [37] | 59.5 (14.4) PDQ-39 | 46.4 (14.5)* (12 mo) PDQ-39 49.2 (10.3)* (24 mo) PDQ-39 | nr | nr |
Safety and Tolerability
Study | Most frequent AEsa | SAEs and AEs leading to discontinuation |
---|---|---|
Lopiano et al. 2019 [51] | nr | SAEs in ≥ 1% of patients (not related): Pneumonia 2.8%; femur fracture 2.1%; cardiac failure 2.1%; cardiac arrest 1.4%; peripheral neuropathy 1.4%; worsening of PD 1.4%; peritonitis 1.4%; death 1.4%; fasciitis 1.4% SAEs in ≥ 1% of patients (related to PEG/J or device): Wrong technique in drug usage process 1.4% AEs leading to discontinuation in ≥ 1% of patients: Device occlusion/complication 1.4%; abnormal weight loss/hypoglycaemia 1.4%; fasciitis 1.4%; peripheral sensory neuropathy 1.4% |
Fabbri et al. 2019 [49] | nr | nr |
Zibetti et al. 2018 [27] | nr | nr |
Fernandez et al. 2018 [48] | ≥ 15% of patients:b Postoperative wound infection 23%; vitamin B6 decreased 22%; fall 21%; urinary tract infection 19%; blood homocysteine increased 18%; excessive granulation tissue 16%; incision-site erythema 15% | SAEs in ≥ 3% of patients:b Pneumonia 6%; complication of device insertion 5%; fall 5%; pneumonia aspiration 3%; post-operative wound infection 3%; weight decreased 3% AEs leading to discontinuation in ≥ 2% of patients: Complication of device insertion 2%; death of unknown cause 2%; pneumonia 2% |
Standaert et al. 2017 [50] | ≥ 15% of patients:b Procedural pain 33%; stoma site infection 28%; stoma site pain 23%; anxiety 21%; stoma site erythema 21%; fall 18%; weight decreased 18%; urinary tract infection 15% | SAEs in ≥ 3% of patients:b Acute respiratory failure 3%; anxiety 3%; atrial fibrillation 3%; aspiration pneumonia 3%; basal cell carcinoma 3%; congestive cardiac failure 3%; internal hernia 3%; major depression 3%; osteoarthritis 3%; peritonitis 3%; radiculopathy 3%; respiratory distress 3%; sedation 3%; suicidal ideation 3% AEs leading to discontinuation in ≥ 2% of patients: Stoma site pain or infection 5%; cognitive disorder 3%; pneumonia 3%; congestive cardiac failure, acute respiratory failure and aspiration pneumonia following spinal surgery 3% |
Antonini et al. 2017 [19] | ≥ 4% of patients:c Weight decrease 6.7%; device related infection 5.9%; device dislocation 4.8%; device issue 4.8%; polyneuropathy 4.5% | SAEs in ≥ 1% of patients:c Device dislocation 2.2%; device issue 2.0%; Parkinson’s disease 2.0%; parkinsonism 2.0%; device complication 1.7%; device malfunction 1.4%; device occlusion 1.4%; abdominal pain 1.1%; hallucination 1.1%; pneumonia 1.1%; polyneuropathy 1.1% Most common AE leading to discontinuation: Device dislocation 0.6% |
De Fabregues et al. 2017 [38]c | ≥ 30% of patients:c Pharmacological: Leg pain 40.5%; polyneuropathy 35.1%; psychosis/hallucinations 35.1%; vitamin B6 deficit 32.4% PEG procedures gastrostomy: Granuloma 37.8%; abdominal pain/nausea/vomiting 32.4%; stoma dermatitis 32.4% Infusion device: PEG replacement 91.2%; transitory or permanent obstruction of intestinal tube 35.1% | SAEs in ≥ 3% of patients:c PEG removal 10.8%; stoma infection 8.1%; PEG hooked related to infusion device 8.1%; dyskinesia 8.1%; weight loss 8.1%; freezing in ‘on’ 5.4% AEs leading to discontinuation in ≥ 2% of patients: Intolerance to the administration system 5.4%; serious stoma infection 2.7%; worsening of dyskinesia 2.7% |
Juhasz et al. 2017 [39] | ≥ 5% of patients:c Drug related: Weight decreased 14.7%; hallucination/confusion 11.8%; symptomatic orthostatic hypotension 8.8%; polyneuropathy 5.9% Surgery related: Abdominal pain 70.6%; injection site reaction 14.7%; wound infection 8.8%; peritonitis 5.9% Stoma related: Granuloma infection 23.5%; stoma infection 8.8% Device related: Tube replacement 11.8%; dislocation 8.8% | nr |
Merola et al. 2016 [28] | ≥ 5% of patients:c Infection 20%; weight loss 10%; serous bloody PEG discharge 5%; buried bumper syndrome 5% | nr |
Chang et al. 2016 [40] | ≥ 10% of patients:c Sensorimotor peripheral neuropathy secondary to B12 or B6 deficiency 47%; local tube problems 40%; impulse control disorder or dopamine dysregulation syndrome 27%; stoma infection 13% | nr |
Valldeoriola et al. 2016 [44] | ≥ 10% of patients:c Tube related events 37.3%; local inflammation 23.7%; transient infection 18.1%; pump failure 17.5%; dyskinesia worsening 14.1%; weight loss/anorexia 11.9%; granuloma 11.3%; psychiatric disorder 11.3% | SAEs in ≥ 3% of patients:c Local inflammation 5.1%; tube related events 4.5%; peptic ulcer 3.4%; psychiatric disorders 3.4%; peritonitis 3.4% AEs leading to discontinuation: Related to PEG tube 5.1% |
Calandrella et al. 2015 [29] | ≥ 5% of patients:c Surgery-related: Cardia bleeding 5.7%; PEG breakage 5.7% Device-related: Stoma infection 14.3%; intestinal tube kinking 8.6%; intestinal tube dislocation 8.6% Infusion-related: Peripheral neuropathy 11.4%; worsening of dyskinesias 8.6% | AEs leading to discontinuation in ≥ 2% of patients: Stoma infection 11.4%; worsening of dyskinesias 8.6%; duodenal perforation 2.9%; peritonitis 2.9%; duodenal phytobezoar 2.9% |
Slevin et al. 2015 [41]c | ≥ 20% of patients:c Pump 55%; J tube 50%; stoma site 44%; PEG 36%; incision site erythema 29%; fall 21%; decreased vitamin B6 21% | SAEs in ≥ 3% of patients:c Complication of device insertion 5%; abdominal pain 3%; asthenia 3%; pneumonia 3% AEs leading to discontinuation: Bipolar disorder 1.6%; renal mass 1.6%; intestinal perforation 1.6% |
Fernandez et al. 2015 [20] | ≥ 20% of patients:b Complication of device insertion 34.9%; abdominal pain 31.2%; procedural pain 20.7% | SAEs in ≥ 2% of patients:b Complication of device insertion 6.5%; abdominal pain 3.1%; peritonitis 2.8%; polyneuropathy 2.8%; Parkinson’s disease 2.5%; pneumoperitoneum 2.5% AEs leading to discontinuation in ≥ 1% of patients: Complication of device insertion 1.7% |
Buongiorno et al. 2015 [45] | ≥ 5% of patients:c Drug-related: Hallucination/confusion 18.1%; troublesome dyskinesia 18.1%; weight loss 6.9% Device-related: Intestinal tube kinking 18.1%; tube and connection issue 18.1%; bezoar 6.9% PEG-related: Pump breakage/malfunction 16.7%; pneumoperitoneum 12.5%; wound infection 6.9% | nr |
Caceres-Redondo et al. 2014 [30] | ≥ 10% of patients:c Drug-related: Peripheral neuropathy 13.8% Device-related: Intestinal tube dislocation 27.6% Gastrostomy-related: Peristomal infection 34.5%; granuloma 17.2% | nr |
Zibetti et al. 2014 [31] | ≥ 5% of patients:c Related to LCIG: Weight loss 16.9%; polyneuropathy 6.8% Infusion device related: Tube dislocation 49.2%; occlusion or kinking 27.1%; PEG retention failure 10.2% PEG damage 6.8% Gastrostomy-related: Peristomal infections 23.7% | AEs leading to discontinuation in ≥ 1% of patients: Device problems 12% |
Sensi et al. 2014 [32] | ≥ 5% of patients:c Related to levodopa: Polyneuropathy 32.1%; weight loss 10.7%; hallucinations 10.7%; agitation 10.7%; mood disturbance 7.1% Related to procedure: Peritonitis 7.1% Related to device: Pump failure 17.9%; dislocation/replacement of jejunal tube 14.3%; granulation at PEG puncture 14.3%; tube occlusion 7.1% | nr |
Lundqvist et al. 2014 [46] | ≥ 10% of patients:c Technical/surgery related: Tube dislocations/leakage 60%; local pain around stoma/local chemical peritonitis not requiring treatment 30%; tube occlusions 20%; stoma infections/secretion from stoma 20% Medication related: Hallucinations 40%; minor depression 30%; diarrhoea 10%; leg cramps 10%; increased dyskinesia 10% | SAEs:b Paranoid psychotic reaction; atrial flutter; knotted intestinal tube |
Antonini et al. 2013 [33] | ≥ 5% of patients:c Device-related: Tube dislocation 22.4%; tube occlusion 15.3%; PEG problems, repositioning, replacement 9.2%; granulation at PEG puncture 6.1%; buried bumper syndrome 5.1% | AEs leading to discontinuation in ≥ 1% of patients: PEG problems 2.0%; stoma infection 2.0%; polyneuropathy 2.0% |
Zibetti et al. 2013 [34] | ≥ 2 events:d Device-related: Dislocation of intestinal tube 34; intestinal tube kinking or obstruction 24; PEG internal retention failure 12; PEG pulled out accidently 6 Gastrostomy-related: Peristomal infection 12; intestinal volvulus 2 | nr |
Foltynie et al. 2013 [42] | nr | AEs leading to discontinuation: PEG problems 18.2% |
Fasano et al. 2012 [47] | ≥ 5% of patients:c Device- or drug-related: Inner tube dislocation 14.3%; transient confusion 14.3%; axonal neuropathy 7.1%; occlusion 7.1%; severe constipation 7.1%; PEG infection 7.1%; weight loss 7.1% | |
Merola et al. 2011 [35] | ≥ 10% of patients:c Accidental removal of PEG tube 55%; infection 15%; weight loss 15%; dislocation of intestinal tube 10% | nr |
Antonini et al. 2010 [36] | Device-related:c Tube occlusion 21.1%; tube dislocation 10.5% | nr |
Antonini et al. 2008 [37]d | nr | AEs leading to discontinuation: Dislocation of tube 4.5%; psychosis 4.5%; severe polyneuropathy 4.5% |
Eggert et al. 2008 [43] | ≥ 10% of patients:c Occlusion of the tube 46.2%; disconnection of the tube 30.8%; dislocation of the tube from jejunum to stomach 23.1%; infection of the stoma 23.1%; backache due to the pump weight 15.4% | AEs leading to discontinuation: PEG or infusion device problems 23.1%; difficulties handling the pump 7.7% |