The Long-Term Impact of Levodopa/Carbidopa Intestinal Gel on 'Off'-time in Patients with Advanced Parkinson's Disease: A Systematic Review

Abstract

Introduction: Levodopa/carbidopa intestinal gel (LCIG; carbidopa/levodopa enteral suspension) has been widely used and studied for the treatment of motor fluctuations in levodopa-responsive patients with advanced Parkinson's disease (PD) when other treatments have not given satisfactory results. Reduction in 'off'-time is a common primary endpoint in studies of LCIG, and it is important to assess the durability of this response. This systematic literature review was conducted to qualitatively summarise the data on the long-term effects of LCIG therapy on 'off'-time.

Methods: Studies were identified by searching PubMed, EMBASE and Ovid on 30 September 2019. Studies were included if they reported on patients with PD, had a sample size of ≥ 10, LCIG was an active intervention and 'off'-time was reported for ≥ 12 months after initiation of LCIG treatment. Randomised clinical trials, retrospective and prospective observational studies, and other interventional studies were included for selection. Data were collected on: 'off'-time (at pre-specified time periods and the end of follow-up), study characteristics, Unified Parkinson's Disease Rating Scale (UPDRS) II, III and IV total scores, dyskinesia duration, quality of life scores, non-motor symptoms and safety outcomes.

Results: Twenty-seven studies were included in this review. The improvement in 'off'-time observed shortly after initiating LCIG was maintained and was statistically significant at the end of follow-up in 24 of 27 studies. 'Off'-time was reduced from baseline to end of follow-up by 38-84% and was accompanied by a clinically meaningful improvement in quality of life. Stratified analysis of 'off'-time demonstrated mean relative reductions of 47-82% at 3-6 months and up to 83% reduction at 3-5 years of follow-up. Most studies reported significant improvements in activities of daily living and motor complications. Most frequent adverse events were related to the procedure or the device.

Conclusion: In one of the largest qualitative syntheses of published LCIG studies, LCIG treatment was observed to provide a durable effect in reducing 'off'-time.

Infographic: Video Abstract.

Keywords: Advanced Parkinson’s disease; LCIG; Long-term; ‘Off’-time.

Fig. 1

PRISMA flow chart showing identification and selection of studies

Fig. 2

Percentage reduction in ‘off’-time from baseline to last follow-up in the studies included in this review. *Denotes non-significant change from baseline, all other changes are statistically significant. ^‡‘Off’-time improvement at end of follow-up of each individual study (minimum 12 months; range 12–120 months). Horizontal dotted line represents the weighted average reduction in ‘off’-time across all studies. HCP healthcare professional. UPDRS Unified Parkinson’s Disease Rating Scale

Fig. 3

Percentage reduction in ‘off’-time from baseline plotted against the improvement in health-related quality of life (HRQoL according to PDQ-39 or PDQ-8) in the studies reporting both endpoints at end of follow-up. a Change in HRQoL as percentage change from baseline; b change in HRQoL as actual change in PDQ score from baseline. *Denotes statistically significant change from baseline in HRQoL (p < 0.05). ^‡Horvath et al. [66]. HRQoL health-related quality of life. 1. Standaert et al. 2017 [50]. 2. Antonini et al. 2017 [19]. 3. De Fabregues et al. 2017 [38]. 4. Juhasz et al. 2017 [39]. 5. Chang et al. 2016 [40]. 6. Caceres-Redondo et al. 2014 [30]. 7. Sensi et al. 2014 [32]. 8. Antonini et al. 2013 [33]. 9. Zibetti et al. 2013 [34]. 10. Foltynie et al. 2013 [42]. 11. Fasano et al. 2012 [47]. 12. Antonini et al. 2008 [37]